2-Arylamino-pyrimidines for the treatment of gsk3-related disorders

ABSTRACT

An aqueous solution for prophylactic treatment of teats of lactating mammals, comprising as a first component at least partially deacetylated chitosan, or an acid addition salt thereof, in a concentration of up to about 2% by weight of chitosan, the solution having a pH of from about 4 to about 6.8, and said first component having a molecular weight such that the viscosity of the solution is less than about 50 mPas; and a method of prophylactic treatment of teats of lactating mammals.

FIELD OF INVENTION

[0001] The present invention relates to a new use of pyrimidinederivatives, as a free base or a pharmaceutically acceptable saltthereof in the manufacture of a medicament in the treatment and/orprophylaxis of conditions associated with glycogen synthase kinase-3.The present invention further relates to a method of treatment and/orprophylaxis of conditions associated with glycogen synthase kinase-3,comprising administering to a mammal, including man in need of suchprevention and/or prophylaxis a therapeutically effective amount of saidpyrimidine derivatives. In addition, the present invention relates tonew compounds suitable for the inhibition of glycogen synthase kinase-3.

BACKGROUND OF THE INVENTION

[0002] Glycogen synthase kinase 3 (GSK3) is a serine/threonine proteinkinase composed of two isoforms (α and β), which are encoded by distinctgenes but are highly homologous within the catalytic domain. GSK3 ishighly expressed in the central and peripheral nervous system. GSK3phosphorylates several substrates including tau, β-catenin, glycogensynthase, pyruvate dehydrogenase and elongation initiation factor 2b(eIF2b). Insulin and growth factors activate protein kinase B, whichphosphorylates GSK3 on serine 9 residue and inactivates it.

[0003] Alzheimer's Disease (AD) Dementias, and Taupathies.

[0004] AD is characterized by cognitive decline, cholinergic dysfunctionand neuronal death, neurofibrillary tangles and senile plaquesconsisting of amyloid-β deposits. The sequence of these events in AD isunclear, but believed to be related. Glycogen synthase kinase 3β (GSK3β)or Tau (τ) phosphorylating kinase selectively phosphorylates themicrotubule associated protein τ in neurons at sites that arehyperphosphorylated in AD brains. Hyperphosphorylated protein τ haslower affinity for microtubules and accumulates as paired helicalfilaments, which is the main component that constitute neurofibrillarytangles and neuropil threads in AD brains. This results indepolymerization of microtubules, which leads to dying back of axons andneuritic dystrophy. Neurofibrillary tangles are consistently found indiseases such as AD, amyotrohic lateral sclerosis, parkinsonism-dementiaof Gaum, corticobasal degeneration, dementia pugilistica and headtrauma, Down's syndrome, postencephalatic parkinsoism, progressivesupranuclear palsy and Pick's Disease, Niemann-Pick Disease. Addition ofamyloid-β to primary hippocampal cultures results inhyperphosphorylation of τ and a paired helical filaments-like state viainduction of GSK3β activity, followed by disruption of axonal transportand neuronal death (Imahori and Uchida., J. Biochem 121:179-188, 1997).GSK3β preferentially labels neurofibrillary tangles and has been shownto be active in pre-tangle neurons in AD brains. GSK3 protein levels arealso increased by 50% in brain tissue from AD patients. Furthermore,GSK3β phosphorylates pyruvate dehydrogenase, a key enzyme in theglycolytic pathway and prevents the conversion of pyruvate toacetyl-Co-A (Hoshi et al., PNAS 93:2719-2723, 1996). Acetyl-Co-A iscritical for the synthesis of acetylcholine, a neurotransmitter withcognitive functions. Thus, GSK3β inhibition may have beneficial effectsin progression as well as the cognitive deficits associated withAlzheimer's disease and other above-referred to diseases.

[0005] Chronic and Acute Neurodegenerative Diseases.

[0006] Growth factor mediated activation of the PI3K/Akt pathway hasbeen shown to play a key role in neuronal survival. The activation ofthis pathway results in GSK3β inhibition. Recent studies (Bhat et. al.,PNAS 97:11074-11079, 2000) indicate that GSK3β activity is increased incellular and animal models of neurodegeneration such as cerebralischemia or after growth factor deprivation. For example, the activesite phosphorylation was increased in neurons vulnerable to apoptosis, atype of cell death commonly thought to occur in chronic and acutedegenerative diseases such as Alzheimer's Disease, Parkinson's Disease,amyotrophic lateral sclerosis, Huntington's Disease and HIV dementia,ischemic stroke and head trauma. Lithium was neuroprotective ininhibiting apoptosis in cells and in the brain at doses that resulted inthe inhibition of GSK3β. Thus GSK3β inhibitors could be useful inattenuating the course of neurodegenerative diseases.

[0007] Bipolar Disorders (BD)

[0008] BD's are characterised by manic episodes and depressive episodes.Lithium has been used to treat BD based on its mood stabilising effects.The disadvantage of lithium is the narrow therapeutic window and thedanger of overdosing that can lead to lithium intoxication. The recentdiscovery that lithium inhibits GSK3 at therapeutic concentrations hasraised the possibility that this enzyme represents a key target oflithium's action in the brain (Stambolic et al., Curr. Biol.6:1664-1668, 1996; Klein and Melton; PNAS 93:8455-8459, 1996).Inhibition of GSK3β may therefore be of therapeutic relevance in thetreatment of BD as well as in AD patients that have affective disorders.

[0009] Schizophrenia

[0010] GSK3 is involved in signal transduction cascades of multiplecellular processes, particularly during neural development. Kozlovsky etal (Am J Psychiatry 2000 May;157(5):831-3) found that GSK3β levels were41% lower in the schizophrenic patients than in comparison subjects.This study indicates that schizophrenia involves neurodevelopmentalpathology and that abnormal GSK3 regulation could play a role inschizophrenia. Furthermore, reduced β-catenin levels have been reportedin patients exhibiting schizophrenia (Cotter et al., Neuroreport9:1379-1383, 1998).

[0011] Diabetes

[0012] Insulin stimulates glycogen synthesis in skeletal muscles via thedephosphorylation and thus activation of glycogen synthase. Underresting conditions, GSK3 phosphorylates and inactivates glycogensynthase via dephosphorylation. GSK3 is also over-expressed in musclesfrom Type II diabetic patients (Nikoulina et. al. Diabetes 2000February;49(2):263-71). Inhibition of GSK3 increases the activity ofglycogen synthase thereby decreasing glucose levels by its conversion toglycogen. GSK3 inhibition may therefor be of therapeutic relevance inthe treatment of Type I and Type II Diabetes and Diabetic neuropathy.

[0013] Hair Loss

[0014] GSK3 phosphorylates and degrades β-catenin. β-catenin is aneffector of the pathway for keratonin synthese. β-catenin stabilisationmay be lead to increase hair development. Mice expressing a stabilisedβ-catenin by mutation of sites phosphorylated by GSK3 undergo a processresembling de novo hair morphogenesis (Gat et al., Cell 1998 Nov. 25;95(5):605-14)). The new follicles formed sebaceous glands and dermalpapilla, normally established only in embryogenesis. Thus GSK3inhibition may offer treatment for baldness.

[0015] Oral Contraceptives

[0016] Vijajaraghavan et al. (Biol Reprod 2000 June; 62 (6):1647-54)reported that GSK3 is high in motile versus immotile sperm.Immunocytochemistry revealed that GSK3 is present in the flagellum andthe anterior portion of the sperm head. These data suggest that GSK3could be a key element underlying motility initiation in the epididymisand regulation of mature sperm function. Inhibitors of GSK3 could beuseful as contraceptives for males.

SUMMARY OF THE INVENTION

[0017] According to an aspect of the present invention, there isprovided the use of a compound of formula (I) as a free base or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment and/or prophylaxis of conditions associatedwith GSK3.

[0018] According to another aspect of the present invention, there isprovided a method of treatment and/or prophylaxis of conditionsassociated with GSK3 comprising administering to a mammal, including manin need of such treatment and/or prophylaxis a therapeutically effectiveamount of a compound of formula (I) as a free base or a pharmaceuticallyacceptable salt thereof.

[0019] According to yet another aspect of the present invention, thereis provided a pharmaceutical formulation for use in the treatment and/orprophylaxis of conditions associated with GSK3 comprising atherapeutically effective amount of a compound of formula (I) as a freebase or a pharmaceutically acceptable salt thereof and conventionalexcipients.

[0020] In addition, the present invention relates to new compoundssuitable for the inhibition of glycogen synthase kinase-3.

DETAILED DESCRIPTION OF THE INVENTION

[0021] It has now suprisingly been found that the group of pyrimidinederivatives as decribed below are well suited for inhibiting glycogensynthase kinase-3. The use of said glycogen synthase kinase-3 inhibitorsare suitable in the treatment and/or prophylaxis of conditionsassociated with especially, dementia, Alzheimer's Disease, Parkinson'sDisease, Frontotemporal dementia Parkinson's Type, Parkinson dementiacomplex of Guam, HIV dementia, diseases with associated neurofibrillartangle pathologies, amyotrophic lateral sclerosis, corticobasaldegeneration, dementia pugilistica, Down's syndrome, Huntington'sDisease, postencephelatic parkinsonism, progressive supranuclear palsy,Pick's Disease, Niemann-Pick's Disease, stroke, head trauma and otherchronic neurodegenerative diseases, Bipolar Disease, affectivedisorders, depression, schizophrenia, cognitive disorders, Type I andType II Diabetes and Diabetic neuropathy, hair loss and contraceptivemedication.

[0022] In one aspect of the present invention use is made of a GSK3inhibitor of the general formula (I) in the manufacturing of amedicament for the treatment and/or prophylaxis of conditions associatedwith glycogen synthase kinase-3,

[0023] wherein:

[0024] Ring A is imidazo[1,2a]pyrid-3-yl or pyrazolo[2,3a]pyrid-3-yl;

[0025] R² is attached to a ring carbon and is selected from halo, nitro,cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0, 1 or 2, C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl,N,N-(C₁₋₆alkyl)₂sulphamoyl, phenyl, heterocyclic group, phenylthio or(heterocyclic group)thio; wherein any C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, phenyl or heterocyclic group may be optionally substitutedon carbon by one or more G; and wherein if said heterocyclic groupcontains an —NH— moiety that nitrogen may be optionally substituted by agroup selected from Q;

[0026] m is 0, 1, 2, 3, 4 or 5; wherein the values of R² may be the sameor different;

[0027] R¹ is halo, nitro, cyano, hydroxy, trifluoromethyl,trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₃alkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, C₁₋₃alkoxy, C₁₋₃alkanoyl,N-(C₁₋₃alkyl)amino, N,N-(C₁₋₂alkyl)₂amino, C₁₋₃alkanoylamino,N-(C₁₋₃alkyl)carbamoyl, N,N-(C₁₋₂alkyl)₂carbamoyl, C₁₋₃alkylS(O)_(a)wherein a is 0, 1 or 2, N-(C₁₋₃alkyl)sulphamoyl orN,N-(C₁₋₃alkyl)₂sulphamoyl; wherein any C₁₋₂alkyl, C₁₋₃alkyl,C₂₋₃alkenyl or C₂₀.3alkynyl may be optionally substituted on carbon byone or more J;

[0028] n is 0, 1 or 2, wherein the values of R¹ may be the same ordifferent;

[0029] Ring B is phenyl or phenyl fused to a C₅₋₇cycloalkyl ring;

[0030] R³ is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl, C₁₋₆alkoxy;

[0031] p is 0, 1, 2, 3 or 4; wherein the values of R³ may be the same ordifferent;

[0032] R⁴ is a group A-E-; wherein

[0033] A is selected from hydrogen, C₁₋₆alkyl, phenyl, a heterocyclicgroup, C₃₋₈cycloalkyl, phenylC₁₋₆alkyl, (heterocyclic group)C₁₋₆alkyl orC₃₋₈cycloalkylC₁₋₆cycloalkyl; which C₁₋₆alkyl, phenyl, a heterocyclicgroup, C₃₋₈cycloalkyl, phenylC₁₋₆alkyl, (heterocyclic group)C₁₋₆alkyl orC₃₋₈cycloalkylC₁₋₆cycloalkyl may be optionally substituted on carbon byone or more D; and wherein if said heterocyclic group contains an —NH—moiety that nitrogen may be optionally substituted by a group selectedfrom R;

[0034] E is a direct bond or —O—, —C(O)—, —OC(O)—, —C(O)O—,—N(R^(a))C(O)—, —C(O)N(R^(a))—, —N(R^(a))—, —S(O)_(r)—, —SO₂N(R^(a))— or—N(R^(a))SO₂—; wherein R^(a) is hydrogen or C₁₋₆alkyl optionallysubstituted by one or more D and r is 0, 1 or 2;

[0035] D is independently selected from oxo, halo, nitro, cyano,hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₁alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0, 1 or 2,C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylamino, benzyloxycarbonylamino,N-(C₁₋₆alkyl)sulphamoyl and N,N-(C₁₋₆alkyl)₂sulphamoyl; wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl or phenyl may be optionallysubstituted on carbon by one or more K;

[0036] q is 0, 1 or 2; wherein the values of R⁴ may be the same ordifferent; and wherein p+q≦5;

[0037] G, J and K are independently selected from halo, nitro, cyano,hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl,mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy,methylamino, ethylamino, dimethylamino, diethylamino,N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl,methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl,ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl,N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl orN-methyl-N-ethylsulphamoyl; and

[0038] Q and R are independently selected from C₁₋₄alkyl, C₁₋₄alkanoyl,C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonyl, carbamoyl,N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl; as a free base or apharmaceutically acceptable salt thereof.

[0039] Listed below are definitions of various terms used in thespecification and claims to describe the present invention.

[0040] For the avoidance of doubt it is to be understood that where inthis specification a group is qualified by ‘hereinbefore defined’ or‘defined hereinbefore’ or ‘defined above’ the said group encompasses thefirst occurring and broadest definition as well as each and all of thepreferred definitions for that group.

[0041] For the avoidance of doubt, the phrase “wherein any C₁₋₆alkyl isoptionally substituted” and other such phrases also includes thepossibility of optional substitution on other groups that contain aC₁₋₆alkyl group, for example a C₁₋₆alkoxy, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl) amino, N,N-(C₁₋₆alkyl)₂amino,C₁alkanoylamino, N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl,C₁₋₆alkylS(O)_(a) wherein a is 0, 1 or 2, C₁₋₆alkoxycarbonyl,C₁₋₆alkoxycarbonylamino, N-(C₁₋₆alkyl)sulphamoyl or aN,N-(C₁₋₆alkyl)₂sulphamoyl.

[0042] For the avoidance of doubt it is to be understood that in thisspecification ‘C₁₋₆’ means a carbon group having 1, 2, 3, 4, 5 or 6carbon atoms.

[0043] In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl groups. C₁₋₆alkyl may bemethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl.

[0044] In this specification, unless stated otherwise, the term“C₃₋₆cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl. A similar convention applies to other radicals, for example“phenylC₁₋₆alkyl” includes phenylC₁₋₄alkyl, benzyl, 1-phenylethyl and2-phenylethyl.

[0045] The term “halo” refers to fluoro, chloro, bromo and iodo.

[0046] Where optional substituents are chosen from “one or more” groupsit is to be understood that this definition includes all substituentsbeing chosen from one of the specified groups or the substituents beingchosen from two or more of the specified groups.

[0047] A “heterocyclic group” is a saturated, partially saturated orunsaturated, mono or bicyclic ring containing 4 to 12 atoms of which atleast one heteroatom is chosen from nitrogen, sulphur or oxygen, whichmay, unless otherwise specified, be carbon or nitrogen linked, wherein a—CH₂— group can optionally be replaced by a —C(O)—, a ring nitrogen atommay optionally bear a C₁₋₆alkyl group and form a quaternary compound ora ring nitrogen and/or sulphur atom may be optionally oxidised to formthe N-oxide and or the S-sulfoxide or desulfione. Suitable examples ofthe term “heterocyclic group” are morpholino, piperidyl, pyridyl,pyranyl, pyrrolyl, isothiazolyl, indolyl, quinolyl, thienyl,1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl,pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl,3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl,pyrazinyl, pyridazinyl, isoxazolyl, N-methylpyrrolyl, 4pyridone,1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine-N-oxide andquinoline-N-oxide. Preferably a “heterocyclic group” is a saturated,partially saturated or unsaturated, mono or bicyclic ring containing 5or 6 atoms of which at least one heteroatom is chosen from nitrogen,sulphur or oxygen, which may, unless otherwise specified, be, carbon ornitrogen linked, wherein a —CH₂— group can optionally be replaced by a—C(O)—, a ring nitrogen atom may optionally bear a C₁₋₆alkyl group andform a quaternary compound or a ring nitrogen and/or sulphur atom may beoptionally oxidised to form the N-oxide and or the S-sulfoxide ordesulfione.

[0048] A suitable value for phenyl fused to a C₅₋₇cycloalkyl ring isindanyl or tetralinyl.

[0049] An example of “C₁₋₆alkanoyloxy” is acetoxy. Examples of“C₁₋₆alkoxycarbonyl” include C₁₋₄alkoxycarbonyl, methoxycarbonyl,ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of “C₁₋₆alkoxy”include C₁₋₃alkoxy, methoxy, ethoxy and propoxy. Examples of“C₁₋₆alkanoylamino” include C₁₋₃alkanoylamino, formamido, acetamido andpropionylamino. Examples of “C₁₋₆alkylS(O)_(a) wherein a is 0, 1 or 2”include C₁₋₄alkylsulphonyl, C₁₋₃alkylS(O)_(a), methylthio, ethylthio,methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples of“C₁₋₆alkanoyl” include C₁₋₄alkanoyl, C₁₋₃alkanoyl, propionyl and acetyl.Examples of “N-C₁₋₆alkylamino” include N-(C₁₋₃alkyl)amino, methylaminoand ethylamino. Examples of “N,N-(C₁₋₆alkyl)₂amino” includeN,N-(C₁₋₂alkyl)₂amino, di-N-methylamino, di-(N-ethyl)amino andN-ethyl-N-methylamino. Examples of “C₂₋₆alkenyl” are C₂₋₃alkenyl, vinyl,allyl and 1-propenyl. Examples of “C₂₋₆alkynyl” are C₂₋₃alkynyl,ethynyl, 1-propynyl and 2-propynyl. Examples of“N-(C₁₋₆alkyl)sulphamoyl” are N-(C₁₋₃alkyl)sulphamoyl,N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of“N-(C₁alkyl)₂sulphamoyl” are N,N-(C₁₋₃alkyl)₂sulphamoyl,N,N-(dimethyl)sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl. Examples of“N-(C₁₋₆alkyl)carbamoyl” are N-(C₁₋₆alkyl)carbamoyl,N-(C₁₋₃alkyl)carbamoyl, methylaminocarbonyl and ethylaminocarbonyl.Examples of “N,N-(C₁₋₆alkyl)₂carbamoyl” are N,N-(C₁₋₄alkyl)carbamoyl,N,N-(C₁₋₂alkyl)₂carbamoyl, dimethylaminocarbonyl andmethylethylaminocarbonyl. Examples of “C₅₋₇cycloalkyl ring” arecyclopropyl and cyclohexyl. Examples of “(heterocyclic group)C₁₋₆alkyl”include pyridylmethyl, 3-morpholinopropyl and 2-pyrimid-2-ylethyl.Examples of “(heterocyclic group)thio” include thienylthio andpyridylthio. Examples of “C₃₋₈cycloalkyl” include cyclopropyl andcyclohexyl. Examples of “C₃₋₈cycloalkylC₁₋₆cycloalkyl” includecyclopropylmethyl and 2-cyclohexylpropyl. Examples of“C₁₋₆alkoxycarbonylamino” include methoxycarbonylamino andt-butoxycarbonylamino.

[0050] A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitable pharmaceuticallyacceptable salt of a compound of the invention is for example an alkalimetal salt, an alkaline earth metal salt, an ammonium salt or a saltwith an organic base which provides a physiologically-acceptable cation.

[0051] The compounds of the formula (a) may be administered in the formof a pro-drug, which is metabolised in vivo to give a compound of theformula (I). Examples of pro-drugs include in vivo hydrolysable estersof a compound of the formula (I) having a carboxy or hydroxy group.

[0052] Some compounds of the formula (I) may have chiral centres and/orgeometric isomeric centres (E- and Z-isomers), and it is to beunderstood that the invention encompasses all such optical,diastereoisomeric and geometric isomers that possess GSK3 inhibitoryactivity.

[0053] The invention also relates to any and all tautomeric forms of thecompounds of the formula (I) that possess GSK3 inhibitory activity.

[0054] Another aspect of the invention relates to novel compounds, whichare;

[0055]2-(4-Fluoro-3-methylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,

[0056] 2-(4-Cyanoanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,

[0057] 2-(4-Chloroanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,

[0058] 2-Anilino-4-(2-methylimidazo[1,2a]pyrid-3-yl)pyrimidine,

[0059]2-[4-(Pyrimid-2-ylaminosulphonyl)anilino]-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,

[0060] 2-(4-Carbamoylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,

[0061] 2-(3-Cyanoanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,

[0062] 2-(3,5-Difluoroanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,

[0063] 2-(3-Chloroanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,

[0064]2-[4-(N,N-Dimethyl-carbamoyl)anilino]-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,

[0065] 2-(4-Mesylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine and

[0066] 2-(3-Sulphamoylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,

[0067] as a free base or pharmaceutically acceptable salt thereof.

[0068] The present invention also relates to the use of the above listedcompounds in the manufacture of a medicament for the treatment and/orprophylaxis of conditions associated with glycogen synthase kinase-3inhibition.

[0069] Methods of Preparation

[0070] Another aspect of the present invention provides a process forpreparing a compound of formula I as a free base or a pharmaceuticallyacceptable salt thereof. The process, (wherein R¹, R², R³, R⁴, X, RingA, Ring C, Ring D, m, p, q and n are, unless otherwise specified, are asdefined in formula I and Ring B is a pyrimidine or a pyridine wherein Pis N or CR¹), comprising:

[0071] a) reacting of a pyrimidine or a pyridine of formula II:

[0072]  wherein L is an amine or a leaving group; with a compound offormula III wherein L is an amine or a leaving group:

[0073] b) reacting a pyrimidine or a pyridine of formula IV:

[0074]  with a compound of the formula V:

[0075]  wherein one of M and Q¹ is a leaving group E and the other is ametallic group Y; or

[0076] c) when P is N, reacting a compound of formula VI:

[0077]  with a compound of formula VII:

[0078]  wherein R⁵ is C₁₋₆alkyl and R¹ is as defined above;

[0079] and thereafter, if necessary:

[0080] i) converting a compound of the formula I into another compoundof the formula I e.g. reduction of X when X is CO to C(OR⁵)R⁶ whereinR⁵═R⁶═hydrogen.

[0081] ii) removing any protecting groups; and

[0082] iii) forming a free base or a pharmaceutically acceptable salt orin vivo hydrolysable ester thereof.

[0083] L is defined as an amino group or leaving groups. Suitableleaving groups are for example, a halo, sulphonyloxy group or a thioether, for example a chloro, bromo, methanesulphonyloxy or atoluenesulphonyloxy group or a thiomethyl ether. One of the L is anamino group and the other is a leaving group.

[0084] A suitable leaving group E is, for example, a halo orsulphonyloxy group, for example a bromo, iodo ortrifluoromethylsulphonyloxy group.

[0085] A suitable metallic group Y, is, for example, copper, lithium, anorganoboron reagent such as B(OH)₂, B(OPr^(i))_or B(Et)₂, or anorganotin compound such as SnBu₃, an organosilicon compound such asSi(Me)F₂, an organozirconium compound such as ZrCl₃, an organoaluminiumcompound such as AlEt₂, an organomagnesium compound such as MgBr, anorganozinc compound such as ZnCl or an organomercury compound such asHgBr.

[0086] Suitable reaction conditions for the above reactions are asfollows:

[0087] a) A compound of formula II and a compound of formula III may bereacted together:

[0088] i) in the presence of a suitable solvent for example a ketonesuch as acetone or an alcohol such as ethanol or butanol or an aromatichydrocarbon such as toluene or N-methyl pyrrolidine, optionally in thepresence of a suitable base for example an inorganic base such aspotassium carbonate or an organic base such as triethyl amine or sodiumbis(trimethylsilyl)amide, or optionally in the presence of a suitableacid for example an inorganic acid such as hydrochloric acid orsulphuric acid, or an organic acid such as acetic acid or formic acid ora suitable Lewis acid and at a temperature in the range of 0° C. to toreflux, preferably at reflux; or

[0089] ii) in the presence of a suitable palladium catalyst such asPdX₂, L^(a) ₂Pd(0) or L^(a) ₂PdX₂, where X stands for a halogen such aschlorine or bromine and L^(a) stands for a suitable ligand such astriphenylphosphine, tri-o-tolylphosphine, trifurylphosphine,triphenylarsine or dibenzylidenacetone and with or without an additionof a ligand L such as triphenylphosphine, tri-o-tolylphosphine,trifurylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene(either as a racemate or as an enantiomer) or triphenylarsine in ansuitable solvent such as dioxane, tetrahydrofuran, toluene, benzene,N,N-dimethylformamide or xylene in the presence of a suitable base suchas cesium carbonate, sodium tert-butoxide or lithiumbis(trimethylsilyl)amide and the reaction may occur at a temperaturebetween +20° C. and +150° C.

[0090] A compound of the formula II may be prepared according to SCHEMEI

[0091] wherein one of M and Q² is a leaving group E as defined above andthe other is a metallic group Y as defined above and L is as definedabove.

[0092] Cross coupling conditions are well known in the art. Suitableconditions include, for example, those described under b) below.

[0093] Compounds of the formula II where Ring A isimidazo[1,2a]pyrid-3-yl and when P is N, may also be prepared accordingto SCHEME II.

[0094] K is a suitable leaving group (for example C₁₋₆alkanoyloxy), R¹and R² are as defined above, m is 0, 1, 2, 3 or 4; Q¹ is a suitableleaving group (for example C₁₋₆alkoxy) and R⁵ is as defined above.

[0095] Where Ring A is pyrazolo[2,3a]pyrid-3-yl compounds of the formulaII and when P is N, may also be prepared according to SCHEME III.

[0096] wherein Q¹, R¹, R² and R⁵ are as defined above.

[0097] Compounds of formula IIf or IIk may be further modified toproduce compounds of formula IIn:

[0098] It will be appreciated by those skilled in the art that compoundsof formula IIn may be additionally modified by standard functional groupmodification reactions known in the art to produce compounds of formulaII where L is as defined above.

[0099] Compounds of formula III, where X is —CO—, may be preparedaccording to SCHEME V,

[0100] by a metal-halogen exchange reaction, in an appropriate anhydroussolvent such as tetrahydrofuran or diethyl ether using a suitablealkyl-lithium or metal e.g. butyllithium, lithium or magnesium turnings,of a compound of formula IIIa, wherein Hal is Cl, Br or I, followed byreaction with a compound of formula IIIb, wherein L is as defined above.The reaction may be performed at a reaction temperature within the rangeof −78° C. to is room temperature.

[0101] Compounds of formula IIa, IIb, IIc, IId, IIh, IIi, IIIa and IIIbare commercially available compounds, or they are known in theliterature, or they are prepared by standard processes known in the art.

[0102] b) Compounds of formula IV and compounds of formula V may bereacted together under standard cross coupling conditions. Examples ofthese are in the presence of a catalyst, for example, a metalliccatalyst such as tetrakis(triphenylphosphine)palladium(0), palladium(II)chloride, palladium(II) bromide, nickel(II) chloride, nickel(II) bromideor bis(triphenylphosphine)nickel(II) chloride, in the presence of asuitable inert solvent or diluent, for example tetrahydrofuran,1,4-dioxan, 1,2-dimethoxyethane, benzene, toluene, xylene, methanol orethanol. The reaction is preferably conducted in the presence of asuitable base such as, for example, sodium carbonate or potassiumcarbonate, pyridine, 4-dimethylaminopyridine, triethylamine ormorpholine, and conveniently at a temperature in the range of, forexample 10 to 250° C., preferably in the range of 60 to 120° C.

[0103] Compounds of formula IV may be prepared according to SCHEME VI

[0104] One of the L is an amino group and the other L is a leavinggroup.

[0105] Compounds of formula V are commercially available compounds, orthey are known in the literature, or they are prepared by standardprocesses known in the art.

[0106] c) Compounds of formula VI and compound of formula VII arereacted together in a suitable solvent such as NV-methylpyrrolidinone orbutanol at a temperature in the range of 100 to 200° C., preferably inthe range of 150 to 170° C. The reaction is preferably conducted in thepresence of a suitable base such as, for example, sodium methoxide orpotassium carbonate.

[0107] Compounds of formula VI and VII are commercially availablecompounds, or they are known in the literature, or they are prepared bystandard processes known in the art, or compounds of formula VII may beprepared by a process similar to that described for IIf and IIkhereinabove.

[0108] It will be appreciated that certain of the various ringsubstituents in the compounds of the present invention may be introducedby standard aromatic substitution reactions or generated by conventionalfunctional group modifications either prior to or immediately followingthe processes mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group. Particularexamples of modifications include the reduction of a nitro group to anamino group by for example, catalytic hydrogenation with a nickelcatalyst or treatment with iron in the presence of hydrochloric acidwith heating; oxidation of alkylthio to alkylsulphinyl oralkylsulphonyl. It will also be appreciated that in some of thereactions mentioned herein it may be necessary/desirable to protect anysensitive groups in the compounds. The instances where protection isnecessary or desirable, suitable methods for protection are known tothose skilled in the art. Conventional protecting groups may be used inaccordance with standard practice (for illustration see T. W. Green, P.G. M. Wutz, Protective Groups in Organic Synthesis, Wiley Interscience,1999). The protecting groups may be removed at any convenient stage inthe synthesis using conventional techniques well known in the chemicalart.

EXAMPLES

[0109] The invention will now be illustrated by the followingnon-limiting examples in which, unless stated otherwise:

[0110] (i) temperatures are given in degrees Celsius (° C.); operationswere carried out at a temperature in the range of 18-25° C., i.e. roomor ambient temperature, if not otherwise indicated;

[0111] ii) organic solutions were dried over anhydrous magnesiumsulphate; evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (600-4000 Pascals; 4.5-30 mmHg) with abath temperature of up to 60° C.;

[0112] (iii) chromatography means flash chromatography on silica gel;thin layer chromatography (TLC) was carried out on silica gel plates;where a silica Bond Elut column is referred to, this means a columncontaining 10 g or 20 g of silica of 40 micron particle size, the silicabeing contained in a 60 ml disposable syringe and supported by a porousdisc, obtained from Varian, Harbor City, Calif., USA under the name“Mega Bond Elut SI”, “Mega Bond Elut” is a trademark;

[0113] (iv) in general, the course of reactions was followed by TLC andreaction times are given for illustration only;

[0114] (v) final products had satisfactory proton nuclear magneticresonance (NMR) spectra and/or mass spectral data;

[0115] (vi) yields are given for illustration only and are notnecessarily those which can be obtained by diligent process development;preparations were repeated if more material was required;

[0116] (vii) when given, NMR data is in the form of delta values givenin parts per million (ppm) relative to tetramethylsilane (TMS) as aninternal standard, determined at 300 MHz or 400 Mhz instrument usingperdeuterio dimethyl sulphoxide (DMSO-d6) or deuterio chloroform (CDCl₃)as solvent unless otherwise indicated;

[0117] (viii) chemical symbols have their usual meanings; SI units andsymbols are used;

[0118] (ix) solvent ratios are given in volume:volume (v/v) terms; and

[0119] (x) mass spectra were run with an electron energy of 70 electronvolts in the chemical ionization (CI) mode using a LC-MS or a directexposure probe; where indicated ionization was effected by electronimpact (EI), fast atom bombardment (FAB) or electrospray (ESP), if nototherwise indicated; values for m/z are given; generally, only ionswhich indicate the parent mass are reported;

[0120] (xi) unless stated otherwise compounds containing anasymmetrically substituted carbon and/or sulphur atom have not beenresolved;

[0121] (xii) where a synthesis is described as being analogous to thatdescribed in a previous example the amounts used are the millimolarratio equivalents to those used in the previous example if not anythingelse is indicated;

[0122] (xiii) the following abbreviations have been used: NMP1-methyl-2-pyrrolidinone; DMF N,N-dimethylformamide; DMFDMAN,N-dimethylformamidedimethylacetyl; DMSO dimethylsulphoxide; THFtetrahydrofuran; and EA elemental analysis.

Example 1

[0123] 2-(3-Chloroanilino)-4-(2-methylimidazo[1,2a]pyrid-3-yl)pyrimidine

[0124] Sodium hydride (236 mg of a 60% suspension in mineral oil, 5.9mmol) was added to a solution of 3-chloroaniline (496 ml, 4.7 mmol) inNMP (10 ml) under nitrogen. The mixture was stirred for 30 minutes atambient temperature and a solution of4-(2-methylimidazo[1,2a]pyrid-3-yl)-2-methylthiopyrimidine (Method 1)(600 mg, 2.3 mmol) in NMP (2 ml) was added. The mixture was heated at150° C. for 3 hours. The reaction mixture was allowed to cool, dilutedwith water and extracted with ethyl acetate. The combined extracts weredried and the volatiles removed by evaporation. The residue was purifiedby chromatography eluting with ethyl acetate/hexane (1:1) increasing inpolarity to ethyl acetate/methanol (97:3). The purified product wastriturated with diethylene ether and hexane, collected by filtration anddried to give the title compound (159 mg, 21% yield). NMR: 2.62 (s, 3H),6.98-7.04 (m, 2H), 7.12 (d, 1H), 7.25 (dd, 1H), 7.42 (dd, 1H), 7.59-7.64(m, 2H), 8.02 (s, 1H), 8.55 (d, 1H), 9.72 (d, 1H), 9.84 (s, 1H).

Examples 2-12

[0125] Following the procedure of Example 1 and using the appropriatestarting materials the following compounds were prepared, m/z ExCompound NMR [MH]⁺  2 2-(4-Sulphamoylanilino)-4-(2- 2.64(s, 3H),7.05(dd, 1H), 7.15-7.20 381 methylimidazo[1,2a]pyrid-3-yl) (m, 3H),7.44(dd, 1H), 7.64(d, 1H), pyrimidine 7.74(d, 2H), 7.92(d, 2H), 8.68(d,1 H), 9.75(d, 1H)  3¹ 2-Anilino-4-(2-methylimidazo 2.64(s, 3H),6.92-7.00(m, 2H), 7.08 302 [1,2a]pyrid-3-yl)pyrimidine (d, 1H), 7.30(dd,1H), 7.40(dd, 1H), 7.60(d, 1H), 7.72(d, 2H), 8.50(d, 1 H), 9.60(s, 1H),9.75(d, 1H)  4 2-(4-Chloroanilino)-4-(2- 2.75(s, 3H), 6.82(dd, 1H),7.01(d, 1 336 methylimidazo[1,2a]pyrid-3-yl) H), 7.22(br s, 1H), 7.30(m,3H), 7.60 pyrimidine (m, 2H), 8.47(d, 1H), 9.53(d, 1H)  5¹2-(3-Chloroanilino)-4-(imidazo 7.02(d, 1H), 7.12(dd, 1H), 7.30(dd, 1 322[1,2a]pyrid-3-yl)pyrimidine H), 7.42(d, 1H), 7.50(dd, 1H), 7.60 (d, 1H),7.75(d, 1H), 8.00(s, 1H), 8.48(d, 1H), 8.61(s, 1H), 9.82(s, 1H)  6¹2-(3,4-Dichloroanilino)-4- 7.15(dd, 1H), 7.50(dd, 2H), 7.58(d, 1(imidazo[1,2a]pyrid-3-yl) H), 7.65(dd, 1H), 7.78(d, 1H), 8.22 pyrimidine(d, 1H), 8.50(d, 1H), 8.62(s, 1H), 9.95(s, 1H)  72-(4-Sulphamoylanilino)-4- 7.20(d, 3H), 7.55(d, 2H), 8.80(d, 3 367(imidazo[1,2a]pyrid-3-yl) H), 8.95(d, 2H), 8.50(d, 1H), 8.68(s,pyrimidine 1H), 10.05(s, 1H), 10.10(d, 1H)  8¹2-(3-Chloro-4-fluoroanilino)-4- 7.14(dd, 1H), 7.32-7.55(m, 3H), 7.60 340(imidazo[1,2a]pyrid-3-yl) (dd, 1H), 7.78(d, 1H), 8.10(dd, 1H),pyrimidine 8.48(d, 1H), 8.62(s, 1H), 9.82(s, 1H)  92-(2-Chloroanilino)-4-(imidazo 7.08(dd, 1H), 7.17(d, 1H), 7.37(m, 2 322[1,2a]pyrid-3-yl)pyrimidine H), 7.48(dd, 1H), 7.51(br s, 1H), 7.62 (d,1H), 7.76(d, 1H), 8.30(s, 1H), 8.40(m, 1H), 9.81(d, 1H), 9.94(dd, 1H) 102-(2-Chloro-4-methylanilino)-4- 2.38(s, 3H), 6.91(dd, 1H), 7.14(d, 1 336(imidazo[1,2a]pyrid-3-yl) H), 7.28(br s, 1H), 7.38(m, 2H), 7.61pyrimidine (s, 1H), 7.73(d, 1H), 8.16(d, 1H), 8.28(s, 1H), 8.40(d, 1H),9.78(d, 1 H) 11¹ 2-[4-(3,5-Dioxapiperidin-1-yl) 4.87(s, 2H), 5.20(s,4H), 7.16(dd, 1 439 sulphonylanilino]-4-(imidazo H), 7.51(d, 2H),7.75(d, 1H), 7.83(d, [1,2a]pyrid-3-yl)pyrimidine 2H), 7.98(d, 2H),8.50(d, 1H), 8.64 (s, 1H) 12^(1, 2) 2-[4-(2-Diethylaminoethoxy) 0.98(t,6H), 2.50-2.62(m, 4H), 403 anilino]-4-(imidazo[1,2a]pyrid-3-2.78-2.82(m, 2H), 4.00(t, 2H), 6.84 yl)pyrimidine (dd, 2H), 7.08(dd,1H), 7.38(d, 1H), 7.48(dd, 1H), 7.60(s, 2H), 7.75(d, 1 H), 8.38(d, 1H),8.59(s, 1H), 9.42(s, 1H)

Example 13

[0126]2-[4-(3-Dimethylamino-2-hydroxypropoxy)anilino]-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0127] A mixture of 4-(3-dimethylamino-2-hydroxypropoxy)aniline (497 mg,1.76 mmol) (Method 11) and cyanamide (185 mg, 4.4 mmol) in NMP (1 ml)was heated at 160° C. for 30 minutes. A mixture of3-(3-dimethylaminoprop-2-en-1-oyl)imidazo[1,2a]pyridine (Method 5) (400mg, 1.76 mmol) and sodium methoxide (183 mg, 3.5 mmol) in 1-butanol (10ml) was then added and the mixture heated at reflux for 3 hours. Themixture was allowed to cool and the residue was purified bychromatography, eluting with ethyl acetate/methanol (97:3 increasing inpolarity to 90:10) to give the title compound (30 mg, 4% yield). NMR:2.35 (s, 6H), 2.40-2.63 (m, 2H), 3.82-4.02 (m, 3H), 6.90 (d, 2H), 7.06(dd, 1H), 7.30 (d, 1H), 7.50 (dd, 1H), 7.59 (s, 2H), 7.74 (d, 1H), 8.38(d, 1H), 8.58 (s, 1H), 9.42 (s, 1H); m/z: 405 [MH]⁺.

Examples 14-15

[0128] Following the procedure of Example 13 and using the appropriatestarting materials the following compounds were prepared, m/z ExCompound NMR [MH]⁺ 14¹ 2-[4-(3-Dimethylamino-2- 2.20(s, 6H),2.26-2.45(m, 2H), 2.65 419 Hydroxypropoxy)anilino]-4-(2- (s, 3H),3.80-3.95(m, 3H), 4.80(s, 1 methylpyrazolo[2,3a]pyrid-3-yl) H), 6.88(d,2H), 7.00(d, 2H), 7.38 pyrimidine (dd, 1H), 7.60(d, 2H), 8.38(d, 1H),8.44(d, 1H), 8.65(d, 1H), 9.21(s, 1H) 15² 2-[4-(3-Dimethylamino-2-2.63(s, 3H), 2.80(s, 6H), 3.12-3.26 419 Hydroxypropoxy)anilino]-4-(2-(m, 2H), 4.27(br s, 1H), 5.93(br s, 1 methylimidazo[1,2,a]pyrid-3-yl)H), 6.90-7.04(m, 4H), 7.40(t, 1H), pyrimidine 7.60(dd, 2H), 8.45(d, 1H),9045(s, 1H), 9.73(d, 1H)

Examples 16-36

[0129] The following examples were prepared, purified and characterisedby the following generic method:

[0130] Sodium bis (trimethylsilyl)amide (2.05 ml of a 1M solution inTHF, 2.05 mmol) was added to a solution of the aniline (1.65 mmol) inNMP (1.5 ml) under nitrogen. The mixture was stirred for 30 minutes atambient temperature and a solution of4-(imidazo[1,2a]pyrid-3-yl)-2-methylthiopyrimidine (Method 4) (200 mg,0.83 mmol) in NMP (1 ml) was added. The reaction mixture was heated at150° C. for 2.5 hours. The solvent and volatiles were removed byevaporation and the residue was purified by chromatography eluting withethyl acetate, then ethyl acetate/methanol (97:3) and finally ethylacetate/methanol (97:3). The reaction products were characterised byHPLC on a 4.6 mm×10 cm Hichrom RPB 100A column elutingwater/acetonitrile/formic acid (95:5:0.1 for 1.5 minutes then on a 10minute gradient to 5:95:0.1) with a flow rate of 1.0 ml/minute,detecting at 254 nm (bandwidth 10 nm). HPLC Ret M/z Ex CompoundTime(mins) [MH]⁺ 16 2-Anilino-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 7.26288 17 2-(2-Fluoroanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 7.26306 18 2-(3-Bromoanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 8.30 36819 2-(3-Fluoroanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 7.70 306 202-(3-Methoxyanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 7.39 318 212-(3-Methylthioanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 7.98 33422 2-(3-Acetylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 7.13 330 232-(3-Ethylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 8.11 316 242-(4-Fluoroanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 7.47 306 252-(4-Chloroanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 8.15 322 262-(4-Methoxyanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 7.02 318 272-(4-Benzyloxyanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 8.65 394 282-[4-(Anilinosulphonyl)anilino]-4-(imidazo[1,2a]pyrid-3-yl) 7.79 443pyrimidine 29 2-(4-Mesylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine6.84 366 302-(4-Methylthioanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 7.89 33431 2-(4-Methylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 7.65 302 322-(3-Sulphamoylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 6.30 36733 2-[4-(Pyrimid-2-ylaminosulphonyl)anilino]-4-(imidazo[1,2a] 6.72 445pyrid-3-yl)pyrimidine 342-(4-Phenoxyanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 8.86 380 352-(3-Methylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 7.63 302 362-(Indan-5-ylamino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine 8.20 328

Example 37

[0131]2-(3-Chloroanilino)-4-(2,5-dimethylimidazo[1,2a]pyrid-3-yl)pyrimidine

[0132] 2-Methylthio-4-(2,5-dimethylimidazo[1,2a]pyrid-3-yl)pyrimidine(Method 14) (200 mg, 0.74 mmol) was added to a solution of3-chloroaniline (0.16 ml, 1.48 mmol) and sodium hydride (60 mg, 1.48mmol) in NMP (1 ml) under nitrogen. The mixture was heated at 150° C.for 4 hours and then allowed to cool. The crude reaction mixture wasloaded onto a Bond Elut column eluting with dichloromethane to removethe NMP and then with dichloromethane/methanol/methylamine (75:20:5) toelute the product. The product was further purified by chromatographyeluting with ethyl acetate/hexane (8:2) and then ethyl acetate to givethe title compound (22 mg, 9% yield). NMR: 2.27 (s, 3H), 2.61 (s, 3H),7.01 (d, 1H), 7.12 (d, 1H), 7.30 (m, 2H), 7.56 (d, 1H), 7.62 (d, 1H),8.57 (d, 1H), 9.41 (s 1H), 9.83 (s, 1H); m/z: 350 [MH]⁺.

Example 38

[0133] Following the procedure of Example 37 and using the appropriatestarting materials the following compound was prepared, m/z Ex CompoundNMR [MH]⁺ 38 2-(3-Chloroanilino)-4-(2- 2.64(s, 3H), 6.95-7.03(m, 2H),7.17 336 methylpyrazolo[2,3a]pyrid-3-yl) (d, 1H), 7.32(d, 1H), 7.44(dd,1H), pyrimidine 7.58-7.64(m, 2H), 8.04(s, 1H), 8.57(d, 1H), 9.72(d, 1H),9.84(s, 1H)

Example 39

[0134]2-[4-(N-Methylsulphamoyl)anilino]-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0135] Toluene (4 ml) was added to a mixture oftris(dibenzideneacetone)dipalladium(0) (24 mg, 0.026 mmol),0.2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (21 mg, 0.034 mmol),2-chloro-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine (Method 20; 150 mg, 0.652mmol) and 4-(N-methylsulphamoyl)aniline (Method 23; 135 mg, 0.725 mmol)under nitrogen. The flask was evacuated and refilled with nitrogen andsodium tert-butoxide (140 mg, 1.46 mmol) was added and the flask wasre-evacuated and refilled with nitrogen. The mixture was heated at 100°C. for 3 hours and then allowed to cool. The mixture was diluted withethyl acetate and washed with water. The organic phase was separated,dried and the volatiles removed by evaporation. The residue was purifiedby chromatography eluting with ethyl acetate/methanol (100:0 increasingin polarity to 97:3) to give the title compound (15 mg, 60% yield). NMR:2.42 (d, 3H), 7.25-7.10 (m, 2H), 7.52-7.45 (m, 2H), 7.79-7.70 (m, 3H),7.98 (d, 2H), 8.50 (d, 1H), 8.62 (s, 1H); m/z: 381 [MH]⁺.

Examples 40-44

[0136] Following the procedure of Example 39 and using the appropriatestarting materials the following compounds were prepared, m/z ExCompound NMR [MH]⁺ SM 40¹ 2-{4-[N-(2-Methoxyethyl) 2.90(q, 2H), 3.18(s,3H), 425 Meth sulphamoyl]anilino}-4- 3.28-3.30(m, 2H), 7.16(dd, 1 24(imidazo[1,2a]pyrid-3-yl) H), 7.48-7.54(m, 3H), 7.71-7.80 pyrimidine (m,3H), 7.95(d, 2H), 8.50(d, 1H), 8.62(s, 1H) 41² 2-[4-(N-Propylsulphamoyl)0.80(t, 3H), 1.34-1.42(m, 2H), 409 Meth anilino]-4-(imidazo[1,2a]2.65-2.75(m, 2H), 7.15(dd, 1H) 25 pyrid-3-yl)pyrimidine 7.17(dd, 1H),7.55-7.48(m, 2 H), 7.70-7.79(m, 3H), 7.95(d, 2H), 8.50(d, 1H), 8.63(s,1H) 42 2-[4-(N-Cyclopropyl- 0.00-0.05(m, 2H), 0.09-0.12(m, 405 Methsulphamoyl)anilino]-4- 2H), 1.70-1.75(m, 1H), 6.79 [M − H]⁻ 26(imidazo[1,2a]pyrid-3-yl) (dd, 1H), 7.10-7.15(m, 2H), pyrimidine7.32-7.42(m, 4H), 7.60(d, 2H), 8.12(d, 1H), 8.28(s, 1H), 9.74 (s, 1H),9.75(s, 1H) 43 2-[4-(N,N-Dimethyl- 2.98(s, 6H), 7.10(dd, 1H), 359carbamoyl)anilino]-4- 7.3.8-7.50(m, 3H), 7.72-7.82(m,(imidazo[1,2a]pyrid-3- 3H), 8.45(d, 1H), 8.61(s, 1H), yl)pyrimidine9.82(s, 1H) 44³ 2-[4-(N-Methylcarbamoyl) 2.78(d, 3H), 7.15(dd, 1H), 7.43345 anilino]-4-(imidazo[1,2a] (d, 1H), 7.50(dd, 1H), 7.75-7.82pyrid-3-yl)pyrimidine (m, 5H), 8.24(d, 1H), 8.48(d, 1 H), 8.62(s, 1H),9.90(s, 1H)

Example 45

[0137]2-{4-[N-(3-Hydroxypropyl)sulphamoyl]anilino}-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0138] 2-Anilino-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine (Example 16; 100mg, 0.347 mmol) was dissolved in thionyl chloride (41 ml) and themixture was cooled to 5° C. Chlorosulphonic acid (0.06 ml, 0.90 mmol)was added and the mixture was stirred at 5° C. for 30 minutes, thenallowed to warm to ambient temperature and stirred for 60 minutes. Themixture was then heated at reflux for 90 minutes. The volatiles wereremoved by evaporation and the residue azeotroped with toluene.3-Aminopropanol (3 ml) was added to the residue and the mixture stirredat ambient temperature for 30 minutes. The mixture was purifiedchromatography eluting with hexane/ethyl acetate (50:50) increasing inpolarity to ethyl acetate/methanol (85:15) (60 mg, 41% yield). NMR:1.45-1.56 (m, 2H), 2.79 (q, 2H), 3.35 (q, 2H), 4.39 (t, 1H), 7.15 (dd,1H), 7.31 (t, 1H), 7.45-7.54 (m, 2H), 7.70-7.79 (m, 3H), 7.95 (d, 2H),8.50 (d, 1H), 8.62 (s, 1H); m/z: 423 [M−H]⁻.

Examples 46-50

[0139] Following the procedure of Example 45 and using the appropriatestarting materials the following compounds were prepared, m/z ExCompound NMR [MH]⁺ 46 2-{4-[N-(Cyclopropylmethyl) 0.00-0.04(m, 2H),0.25-0.32(m, 2H), 421 sulphamoyl]anilino}-4-(imidazo 0.70-0.78(m, 1H),2.60(t, 2H), 7.10 [1,2a]pyrid-3-yl)pyrimidine (dd, 1H), 7.28-7.42(m,3H), 7.68-7.75 (m, 3H), 7.87(d, 2H), 8.42(d, 1H), 8.60(s, 1H) 472-{4-[N-(5-Hydroxypentyl) 1.18-1.40(m, 8H), 2.70(t, 2H) 4.25 453sulphamoyl]anilino}-4-(imidazo (br s, 1H), 7.15(dd, 1H), 7.48-7.52(m,[1,2a]pyrid-3-yl)pyrimidine 2H), 7.70-7.78(m, 3H), 7.95(d, 2H), 8.50(d,1H), 8.62(s, 1H) 48 2-(4-{N-[2-(1-Methylpyrrolidin- 1.18-1.25(m, 2H),1.48-1.58(m, 2H), 476 2-yl)ethyl]sulphamoyl}anilino)-4- 1.60-1.70(m,1H), 1.90-2.00(m, 2H), [M − H]⁻ (imidazo[1,2a]pyrid-3-yl) 2.10(s, 3H),2.70-2.85(m, 4H), 7.15 pyrimidine (dd, 1H), 7.40(s, 1H), 7.48-7.53(m, 2H), 7.70-7.80(m, 3H), 7.95(d, 2H), 8.50(d, 1H), 8.63(s, 1H) 492-{4-[N-(3-Diethylaminopropyl) 0.86(t, 6H), 1.42(q, 2H), 2.30(q, 4 480sulphamoyl]anilino}-4-(imidazo H), 2.38-2.42(m, 2H), 2.75(q, 2H),[1,2a]pyrid-3-yl)pyrimidine 7.15(dd, 1H), 7.42-7.55(m, 2H), 7.70-7.80(m,3H), 7.95(d, 2H), 8.50 (d, 1H), 8.65(s, 1H) 502-{4-[N-(2-Isopropylaminoethyl) 0.87(s, 3H), 0.90(s, 3H), 2.46-2.50 452sulphamoyl]anilino}-4-(imidazo (m, 2H), 2.58(q, 2H), 2.80(t, 2H),[1,2a]pyrid-3-yl)pyrimidine 7.18(dd, 1H), 7.48-7.52(m, 2H), 7.70-7.80(m,3H), 7.95(d, 2H), 8.50 (d, 1H), 8.62(s, 1H)

Example 51

[0140]2-(4-{N-[3-(2-Oxopyrolidin-1-yl)propyl]sulphamoyl}anilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0141] 2-Anilino-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine (Example 16; 100mg, 0.347 mmol) was dissolved in thionyl chloride (3 ml) and the mixturewas cooled to 5° C. Chlorosulphonic acid (0.06 ml, 0.90 mmol) was addedand the mixture was stirred at 5° C. for 30 minutes, allowed to warm toambient temperature and stirred for 60 minutes. The mixture was thenheated at reflux for 90 minutes. The volatiles were removed byevaporation and the residue azeotroped with toluene. Pyridine (3 ml) and3-(2-oxopyrolidin-1-yl)propylamine (3 ml) were added to the residue andthe mixture was stirred at ambient temperature for one hour. The mixturewas purified by chromatography eluting with hexane/ethyl acetate (50:50)increasing in polarity to ethyl acetate/methanol (80:20) (60 mg, 36%yield). NMR: 1.51-1.60 (m, 2H), 1.80-1.90 (m, 2H), 2.13 (t, 2H), 2.70(t, 2H), 3.10 (t, 2H), 3.20 (t, 2H), 7.16 (dd, 1H), 7.48-7.55 (m, 2H),7.70-7.80 (m, 3H), 7.95 (d, 2H), 8.50 (d, 1H), 8.62 (s, 1H); m/z:492[MH]⁺.

Examples 52-70

[0142] Following the procedure of Example 45 and using the appropriatestarting materials the following compounds were prepared, m/z ExCompound NMR [MH]⁺ 52 2-{4-[N-(3-Methoxypropyl) 1.55-1.62(m, 2H),2.75-2.81(m, 2H), 439 sulphamoyl]anilino}-4-(imidazo 3.12(s, 3H),3.23-3.28(m, 2H), 7.15 [1,2a]pyrid-3-yl)pyrimidine (dd, 1H), 7.38(t,1H), 7.55(m, 2H), 7.70-7.80(m, 3H), 7.96(d, 2H), 8.50 (d, 1H), 8.62(s,1H) 53 2-{4-[N-(3-Isopropylaminopropyl) 1.48(t, 2H), 1.88(d, 6H),2.42(t, 2H), 466 sulphamoyl]anilino}-4-(imidazo 2.59(m, 1H), 2.79(t,2H), 7.15(dd, 1 [1,2a]pyrid-3-yl)pyrimidine H), 7.48-7.55(m, 2H),7.70-7.80(m, 3 H), 7.95(d, 2H), 8.50(d, 1H), 8.62(s, 1H) 542-{4-[N-(3-Imidazol-1-ylpropyl) 1.80(m, 2H), 2.70(q, 2H), 3.94(t, 2 473sulphamoyl]anilino}-4-(imidazo H), 6.82(s, 1H), 7.08(s, 1H), 7.14(dd, [M− H]⁻ [1,2a]pyrid-3-yl)pyrimidine 1H), 7.48-7.52(m, 4H), 7.70(d, 2H),7.78(d, 1H), 7.98(d, 2H), 8.50(d, 1 H), 8.62(s, 1H) 55¹2-{4-[N-(3-Dimethylaminopropyl) 1.48(m, 2H), 2.02(s, 6H), 2.12(t, 2 452sulphamoyl]anilino}-4-(imidazo H), 2.78(t, 2H), 7.15(dd, 1H), 7.38(s,[1,2a]pyrid-3-yl)pyrimidine 1H), 7.48-7.57(m, 2H), 7.72(d, 2H), 7.78(d,1H), 7.98(d, 2H), 8.50(d, 1 H), 8.62(s, 1H) 562-{4-[N-(3-Morpholinopropyl) 1.52(t, 2H), 2.18-2.22(m, 6H), 2.78 494sulphamoyl]anilino}-4-(imidazo (t, 2H), 3.43-3.48(m, 4H), 7.15(dd, 1[1,2a]pyrid-3-yl)pyrimidine H), 7.38(s, 1H), 7.48-7.55(m, 2H), 7.74(d,2H), 7.78(d, 1H), 7.98(d, 2 H), 8.50(d, 1H), 8.62(s, 1H) 57¹2-{4-[N-(3-Aminopropyl) 1.38-1.45(m, 4H), 2.79(t, 2H), 7.15 424sulphamoyl]anilino}-4-(imidazo (dd, 1H), 7.48-7.56(m, 2H), 7.60-7.64[1,2a]pyrid-3-yl)pyrimidine (m, 1H), 7.72(d, 2H), 7.79(d, 1H), 7.98(d,2H), 8.50(d, 1H), 8.62(s, 1 H) 58¹ 2-(4-{N-[2-(2-Hydroxyethyl 2.75(t,2H), 2.86-2.90(m, 2H), 3.54 454 amino)ethyl]sulphamoyl}anilino)- (t,2H), 3.60(t, 2H), 7.08(d, 2H), 7.18 4-(imidazo[1,2a]pyrid-3-yl) (dd,1H), 7.42-7.55(m, 2H), 7.75-7.80 pyrimidine (m, 3H), 8.00(d, 2H),8.52(d, 1H), 8.62(s, 1H) 59² 2-{4-[N-(2-Imidazol-4-ylethyl) 3.10(t, 2H),3.95(t, 2H), 7.10(d,

H), sulphamoyl]anilino}-4-(imidazo 7.40(s, 2H), 7.50(d, 2H), 7.58(d, 2[1,2a]pyrid-3-yl)pyrimidine H), 7.69(d, 2H), 7.75(d, 1H), 8.45(d, 1H),8.60(s, 1H), 8.79(s, 1H), 9.75 (s, 1H), 10.1(s, 1H) 60¹2-{4-[N-(3-Methylaminopropyl) 1.70-1.78(m, 2H), 2.66(s, 3H), 2.90 436sulphamoyl]anilino}-4-(imidazo (t, 2H), 3.00(t, 2H), 7.08(d, 2H), 7.18[M − H]⁻ [1,2a]pyrid-3-yl)pyrimidine (t, 1H), 7.44(d, 2H), 7.51(m, 1H),7.70-7.80(m, 3H), 8.02(d, 1H), 8.52 (d, 1H), 8.63(s, 1H) 61¹2-{4-[N-(2-Piperazin-1-ylethyl) 2.30(t, 2H), 2.40-2.43(m, 4H), 2.59sulphamoyl]anilino}-4-(imidazo (t, 2H), 2.83-2.90(m, 4H), 7.18(dd, 1[1,2a]pyrid-3-yl)pyrimidine H), 7.49-7.55(m, 2H), 7.68(d, 2H), 7.78(d,1H), 8.02(d, 2H), 8.50(d, 1 H), 8.62(s, 1H) 62¹2-(4-{N-[3-(4-Methylpiperazin- 1.49(m, 2H), 2.10(s, 3H), 2.15-2.25 5071-yl)propyl]sulphamoyl}anilino)- (m, 8H), 2.78(q, 2H), 3.25-3.29(m, 24-(imidazo[1,2a]pyrid-3-yl) H), 7.18(dd, 1H), 7.40(dd, 1H), 7.50pyrimidine (d, 2H), 7.75(d, 2H), 8.80(d, 1H), 7.95(d, 1H), 8.52(d, 1H),8.65(s, 1 H) 63¹ 2-(4-{N-[2-(2-Diethylaminoethyl- 0.93(t, 6H),2.40-2.58(m, 4H), 2.62 509 amino)ethyl]sulphamoyl}anilino)- (t, 2H),2.84(t, 2H), 3.20-3.40(m, 4 4-(imidazo[1,2a]pyrid-3-yl) H), 7.10(d, 1H),7.18(dd, 1H), pyrimidine 7.42-7.50(m, 3H), 7.72-7.80(m, 3H), 7.98(d,2H), 8.50(d, 1H), 8.62(s, 1 H) 64¹ 2-{4-[N-(2,3-Dihydroxypropyl) 2.66(m,1H), 2.86(m, 1H), 3.21-3.30 441 sulphamoyl]anilino}-4-(imidazo (m, 2H),3.46(m, 1H), 4.49(t, 1H), [1,2a]pyrid-3-yl)pyrimidine 4.70(d, 1H),7.18(dd, 1H), 7.24(dd, 1 H), 7.48-7.52(m, 2H), 7.70-7.80(m, 3 H),7.98(d, 2H), 8.50(d, 1H), 8.62(s, 1H) 65 2-{4-[N-(2-Dimethylaminoethyl)2.08(s, 6H), 2.24(t, 2H), 2.82(t, 2H), 438sulphamoyl]anilino}-4-(imidazo 1.7(dd, 1H), 7.30(s, 1H), 7.44-7.54[1,2a]pyrid-3-yl)pyrimidine (m, 2H), 7.70-7.80(m, 3H), 7.95(d, 2 H),8.50(d, 1H), 8.63(s, 1H) 66 2-{4-[N-(2-Morpholinoethyl) 2.34-2.45(m,6H), 2.87-2.95(m, 2H), 478 sulphamoyl]anilino}-4-(imidazo 3.46-3.60(m,4H), 7.09(d, 2H), 7.18 [M − H]⁻ [1,2a]pyrid-3-yl)pyrimidine (dd, 1H),7.42-7.50(m, 3H), 7.74-7.80 (m, 2H), 7.98(d, 2H), 8.50(d, 1H), 8.62(s,1H) 67 2-{4-[N-(2-Pyrrolidin-1-ylethyl) 1.64-1.74(m, 4H), 2.52-2.64(m,6H), 464 sulphamoyl]anilino}-4-(imidazo 2.87-2.92(m, 2H), 7.18(dd, 1H),[1,2a]pyrid-3-yl)pyrimidine 7.44-7.54(m, 3H), 7.72-7.80(m, 3H), 7.98(d,2H), 8.50(d, 1H), 8.62(s, 1 H) 68 2-{4-[N-(2-Methylaminoethyl)2.61-2.64(m, 2H), 2.68(s, 3H), 2.90 424 sulphamoyl]anilino}-4-(imidazo(t, 2H), 7.18(dd, 1H), 7.48-7.58(m, 2 [1,2a]pyrid-3-yl)pyrimidine H),7.68-7.78(m, 4H), 7.95(d, 1H), 8.00(d, 1H), 8.51(d, 2H), 8.64(s, 1 H) 692-{4-[N-(2-Piperidin-1-ylethyl) 1.28-1.40(m, 2H), 1.40-1.58(m, 4H), 478sulphamoyl]anilino}-4-(imidazo 2.20-2.50(m, 6H), 2.84-2.92(m, 2H),[1,2a]pyrid-3-yl)pyrimidine 7.18(dd, 1H), 7.48-7.53(d, 2H), 7.72-7.80(m,3H), 7.98(d, 2H), 8.50 (d, 1H), 8.62(s, 1H) 702-{4-[N-(2-Diethylaminoethyl) 0.86(t, 6H), 2.32-2.42(m, 6H), 2.79 466sulphamoyl]anilino}-4-(imidazo (t, 2H), 7.18(dd, 1H), 7.23(s, 1H),[1,2a]pyrid-3-yl)pyrimidine 7.48-7.52(m, 2H), 7.70-7.80(m, 3H), 7.98(d,2H), 8.50(d, 1H), 8.62(s, 1 H)

Example 71

[0143]2-{4-[N-(3-Imidazol-1-ylpropyl)carbamoyl]anilino}-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0144] Toluene (10 ml) was added to2-amino-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine (Method 22; 200 mg, 0.95mmol), 1-[3-(4-bromobenzoylamino)propyl]imidazole (Method 27; 350 mg,1.14 mmol), tris(dibenzideneacetone)dipalladium(0) (43 mg, 0.047 mmol)and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (28 mg, 0.046 mmol)under nitrogen. Sodium tert-butoxide (218 mg, 0.0023 mmol) was added,the reaction mixture was flushed thoroughly with nitrogen and thenheated at 100° C. for 24 hours. The volatiles were removed byevaporation and the residue was purified by chromatography eluting withhexane/ethyl acetate (50:50) increasing in polarity to ethylacetate/methanol (95:5) to give the title compound (99 mg, 24% yield).NMR: 1.90-2.00 (m, 2H), 3.22 (q, 2H), 4.02 (t, 2H), 6.86 (s, 1H), 7.16(dd, 1H), 7.21 (s, 1H), 7.42-7.55 (m, 2H), 6.80 (s, 3H), 7.78 (d, 1H),7.83 (s, 4H), 8.38 (t, 1H), 8.48 (d, 1H), 8.62 (s, 1H), 9.92 (s, 1H);m/z: 439 [MH]⁺.

Examples 72-74

[0145] Following the procedure of Example 71 and using the appropriatestarting materials the following compounds were prepared, m/z ExCompound NMR [MH]⁺ SM 72¹ 2-(4-{N-[3-(2-Oxopyrolidin- 1.70(quin, 2H),1.90(quin, 2H), 456 Meth 1-yl)propyl]carbamoyl} 2.21(t, 2H),3.18-3.24(m, 4H), 28 anilino)-4-(imidazo[1,2a]pyrid- 3.30-3.38(m, 2H),7.15(dd, 1H), 3-yl)pyrimidine 7.42-7.52(m, 2H), 7.78(d, 1H), 7.82(s,4H), 8.27(t, 1H), 8.49(d, 1H), 8.62(s, 1H), 9.90(s, 1H) 73²2-{3-Chloro-4-[N-(2- 3.00(q, 2H), 3.12(s, 3H), 459methoxyethyl)sulphamoyl] 3.25-3.30(m, 2H), 7.18(dd, 1H),anilino}-4-(imidazo[1,2a] 7.50-7.58(m, 2H), 7.68(t, 1H),pyrid-3-yl)pyrimidine 7.75-7.80(m, 2H), 7.87(s, 1H), 8.22(s, 1H),8.55(d, 1H), 8.64(s, 1H) 74³ 2-[3-Chloro-4-(N-propyl 0.80(t, 3H),1.38(m, 2H), 2.79 443 sulphamoyl)anilino]-4- (q, 2H), 7.18(dd, 1H),7.48-7.55 (imidazo[1,2a]pyrid-3-yl) (m, 2H), 7.66(dd, 1H), 7.78(dd 2,pyrimidine H), 7.92(d, 1H), 8.25(s, 1H), 8.55(d, 1H), 8.68(s, 1H), 10.10(d, 1H), 10.26(s, 1H)

Example 75

[0146]2-(3-Methyl-4-sulphamoylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0147] 2-(3-Methylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine(Example 35; 80 mg, 0.266 mmol) was treated as described in Example 45but with 2 M ethanolic ammonia to give the title compound (6 mg, 17%yield). NMR: 2.60 (s, 3H), 6.95-7.20 (m, 4H), 7.46-7.50 (m, 2H),7.70-7.80 (m, 4H), 8.50 (d, 1H), 8.62 (s, 1H), 9.87 (s, 1H); m/z: 381[MH]⁺.

Examples 76-78

[0148] Following the procedure of Example 75 and using the appropriatestarting materials the following compounds were prepared, m/z ExCompound NMR [MH]⁺ 76 2-{3-Methyl-4-[N-(2-methoxy- 2.55(s, 3H), 2.91(q,2H), 3.11(s, 3 439 ethyl)sulphamoyl]anilino}-4- H), 3.22(t, 2H),7.12(dd, 1H), (imidazo[1,2a]pyrid-3-yl) 7.44-7.55(m, 3H), 7.74-7.80(m,4H), pyrimidine 8.50(d, 1H), 8.62(s, 1H), 9.98(s, 1H) 772-{3-Methyl-4-[N-(3-morpholino- 1.49(m, 2H), 2.13-2.20(m, 4H), 508propyl)sulphamoyl]anilino}-4- 3.24-3.32(m, 2H), 2.58(s, 3H), 2.80(imidazo[1,2a]pyrid-3-yl) (t, 2H), 3.42-3.48(m, 4H), 7.12(dd, 1pyrimidine H), 7.48-7.53(m, 2H), 7.75-7.80(m, 4 H), 8.50(d, 1H), 8.62(s,1H) 78 2-{3-Methyl-4-[N-(2-morpholino- 2.18-2.21(m, 4H), 2.30-3.38(m,2H), 494 ethyl)sulphamoyl]anilino}-4- 2.59(s, 3H), 2.87(t, 2H),3.42-3.48 (imidazo[1,2a]pyrid-3-yl) (m, 4H), 7.12(dd, 1H), 7.42-7.55(m,pyrimidine 3H), 7.75-7.80(m, 4H), 8.50(d, 1H), 8.62(s, 1H), 9.98(s, 1H)

Example 79.

[0149]5-Bromo-2-(4-sulphamoylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0150] 2-Anilino-5-bromo-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine (Example97; 73 mg, 0.2 mmol) was treated as described in Example 45 but with 2 Methanolic ammonia to give the title compound (18 mg, 21% yield). NMR:7.12 (dd, 1H), 7.19 (s, 2H), 7.53 (dd, 2H), 7.72 (d, 2H), 7.79 (d, 1H),7.84 (d, 2H), 8.76 (s, 1H), 8.78 (s, 1H), 9.62 (s, 1H); m/z: 445 [MH]⁺.

Examples 80-81

[0151] Following the procedure of Example 79 and using the appropriatestarting materials the following compounds were prepared, m/z ExCompound NMR [MH]⁺ 80 5-Bromo-2-{4-[N-(2-methoxy- 2.90(m, 2H), 3.18(s,3H), 3.28(q, 2 503 ethyl)sulphamoyl]anilino}-4- H), 7.10(dd, 1H),7.48-7.58(m, 2H), (imidazo[1,2a]pyrid-3-yl) 7.70(d, 2H), 7.79(d, 1H),7.86(d, 2 pyrimidine H), 8.76(s, 1H), 8.78(s, 1H), 9.60(d, 1H) 815-Bromo-2-{4-[N-(2-dimethyl- 2.06(s, 6 H), 2.25(t, 2H), 2.82(t, 2H), 516aminoethyl)sulphamoyl]anilino}- 7.15(dd, 1H), 7.30(s, 1H), 7.55(dd, 14-(imidazo[1,2a]pyrid-3-yl) H), 7.72(d, 2H), 7.80(d,1H), 7.90(d,pyrimidine 2H), 8.75(s, 1H), 9.80(s, 1H), 9.65 (d, 1H), 10.28(s, 1H) 82¹5-Bromo-2-{4-[N-(3-dimethyl- 1.70-1.80(m, 2H), 1.87-1.98(m, 2H), 530aminopropyl)sulphamoyl]anilino} 2.62(d, 6 H), 2.79(q, 2H), 7.12(dd, 1-4-(imidazo[1,2a]pyrid-3-yl) H), 7.55(dd, 1H), 7.59(dd, 1H), 7.70pyrimidine (d, 2H), 7.79(d, 1H), 7.90(d, 2H), 8.78(s, 1H), 8.79(s, 1H),9.64(d, 1 H), 10.32(s, 1H)

Example 83

[0152]2-{4-[N-(2-Methoxyethyl)sulphamoyl]anilino}-4-(5-bromoimidazo[1,2a]pyrid-3-yl)pyrimidine

[0153] 2-Anilino-4-(5-bromoimidazo[1,2a]pyrid-3-yl)pyrimidine (Example98; 70 mg, 0.2 mmol) was treated with 2-methoxyethylamine under theconditions described in Example 51 to give the title compound (23 mg,25% yield). NMR: 2.90 (q, 2H), 3.18 (s, 3H), 3.26-3.29 (m, 2H),7.49-7.54 (m, 2H), 7.60 (dd, 1H), 7.74-7.78 (m, 3H), 7.90 (d, 1H), 8.54(d, 1H), 8.62 (s, 1H); m/z: 503 [MH]⁺.

Example 84

[0154]2-{4-[N-(2-Methoxyethyl)sulphamoyl]anilino}-4-(5-phenylthioimidazo[1,2a]pyrid-3-yl)pyrimidine

[0155] Sodium hydride (80 mg of a 60% suspension in mineral oil, 2.0mmol) was added to thiophenol (0.102 ml, 1.0 mmol) in NMP (4 ml) and themixture was stirred for 30 minutes.

[0156]2-[4-(N-(2-Methoxyethyl)sulphamoyl)anilino]-4-(5-bromoimidazo[1,2a]pyrid-3-yl)pyrimidine(Example 83; 100 mg, 0.19 mmol) in NMP (1 ml) was added and the mixturewas heated at 150° C. for 18 hours. The mixture was allowed to cool,diluted with water and extracted with ethyl acetate. The extracts werewashed with water, dried and the volatiles removed by evaporation. Theresidue was triturated with diethylene ether and collected by filtrationto give the title compound (20 mg, 20% yield). NMR: 2;85 (q, 2H), 3.15(s, 3H), 3.24 (q, 2H), 7.10-7.30 (m, 5H), 7.38 (d, 1H), 7;46 (dd, 1H),7.52 (d, 1H), 7.75 (d, 2H), 7.79 (d, 1H), 7.92 (d, 2H), 8.54 (d, 1H),8.66 (s, 1H); m/z: 533 [MH]⁺.

Examples 85-88

[0157] Following the procedure of Example 84 and using the appropriatestarting materials the following compounds were prepared, m/z ExCOMPOUND NMR [MH]⁺ 85¹ 2-{4-[N-(2-Methoxyethyl) 1.18(t, 3H),2.84-2.95(m, 4H), 3.18 485 sulphamoyl]anilino}-4-(5-ethyl- (s, 3H),3.26-3.30(m, 2H), 7.49-7.58 thioimidazo[1,2a]pyrid-3-yl) (m, 3H),7.71-7.79(m, 4H), 7.90(d, 2 pyrimidine H), 8.50-8.55(m, 1H), 8.60(s,1H), 8.89(s, 1H) 86¹ 2-{4-[N-(2-Methoxyethyl) 2.90(t, 2H), 3.05(t, 2H),3.20(s, 3H), 501 sulphamoyl]anilino}-4-[5-(2- 3.32(t, 2H), 3.60(q, 2H),5.00(t, 1H), hydroxyethylthio)imidazo[1,2a] 7.45(dd, 1H), 7.50(d, 1H),7.58(d, 1 pyrid-3-yl]pyrimidine H), 7.70-7.79(m, 3H), 7.95(d, 2H),8.50(d, 1H), 8.59(s, 1H), 9.95(s, 1 H), 10.05(s, 1H) 87²2-{4-[N-(2-Methoxyethyl) 2.90(m, 2H) 3.15(s, 3H), 3.24(q, 2 539sulphamoyl]anilino}-4-[5-(thien-2 H), 7.08-7.10(m, 1H), 7.32(d, 1H),-ylthio)imidazo[1,2a]pyrid-3- 7.42(d, 1H), 7.50(d, 1H), 7.70-7.80yl]pyrirnidine (m, 4H), 7.94(d, 2H), 8.52(d, 1H), 8.63(s, 1H) 88³2-{4-[N-(2-Methoxyethyl) 2.15(s, 6H), 2.40-2.50(m, 2H), 2.90 528sulphamoyl]anilino}-4-[5-(2- (q, 2H), 3.09(t, 2H), 3.20(s, 3H),dimethylaminoethylthio)imidazo 3.28-3.32(m, 2H), 7.48-7.58(m, 3H),[1,2a]pyrid-3-yl]pyrimidine 7.72-7.80(m, 3H), 7.95(d, 2H), 8.51 (d, 1H),8.60(s, 1H), 9.90(s, 1H), 10.11(s, 1H)

Example 89

[0158]2-{4-[N-(2-Methoxyethyl)sulphamoyl]anilino}-4-(5-cyanoimidazo[1,2a]pyrid-3-yl)pyrimidine

[0159]2-{4-[N-(2-Methoxyethyl)sulphamoyl]anilino}-4-(5-bromoimidazo[1,2a]pyrid-3-yl)pyrimidine (Example 83; 87 mg, 0.17 mmol), tetraethylammonium cyanide(27 mg, 0.17 mmol), diphenylphosphinoferrocene (23 mg, 0.03 mmol) copper(1) cyanide (62 mg, 0.7 mmol) and tris(dibenzideneacetone)dipalladium(0)(7 mg, 0.008 mmol) in dry dioxane (6 ml) was flushed thoroughly withnitrogen and heated at reflux for 48 hours. The volatiles were removedby evaporation and the residue was purified by chromatography elutingwith hexane/ethyl acetate (50:50) increasing in polarity to (0:100) togive the title compound (16 mg, 21% yield). NMR: 2.90 (q, 2H), 3.15 (s,3H), 3.25-3.30 (m, 2H), 7.42 (dd, 1H), 7.58 (d, 1H), 7.72-7.78 (m, 3H),7.907.98 (m, 3H), 8.59 (d, 1H), 8.40 (s, 1H), 10.23 (s, 1H), 10.53 (s,1H); m/z: 447 [M−H]⁻.

Example 90

[0160]2-{4-[N-(3-Dimethylaminopropyl)sulphamoyl]anilino}-4-(5-bromoimidazo[1,2a]pyrid-3-yl)pyrimidine

[0161] 2-Anilino-4-(5-bromoimidazo[1,2a]pyrid-3-yl)pyrimidine (Example98; 200 mg, 0.52 mmol) was prepared as described in Example 45 buttreated with 3-dimethylaminopropylamine to give the title compound (92mg, 34% yield). NMR: 1.48-1.58 (m, 2H), 2.10 (s, 6H), 2.20-2.28 (m, 2H),2.72-2.80 (m, 2H), 7.08 (d, 1H), 7.40-7.48 (m, 2H), 7.51 (d, 1H), 7.61(dd, 1H), 7.71-7.78 (m, 3H), 7.90 (d, 2H), 8.55 (d, 1H), 8.64 (s, 1H);m/z: 530 [MH]⁺.

Example 91

[0162]5-(2-Hydroxyethylthio)-2-{4-[N-(2-Methoxyethyl)sulphamoyl]anilino)}-4-(imidazo[1,2a]Pyrid-3-yl)pyrimidine

[0163] Sodium hydride (158 mg of a 60% suspension in mineral oil, 4.0mmol) was added to 2-mercaptoethanol (0.139 ml, 2.0 mmol) in NMP (4 ml)and the mixture was stirred for 30 minutes.

[0164]5-Bromo-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine (Example 80; 100 mg, 0.19 mmol) in NMP (1 ml) was added andthe mixture was heated at 120° C. for 3 hours. The mixture was allowedto cool, diluted with water, neutralised with 2 M hydrochloric acid andextracted with ethyl acetate. The extracts were washed with water andbrine, dried and the volatiles removed by evaporation. The residue waspurified by chromatography eluting with hexane/ethyl acetate (50:50)increasing in polarity to ethyl acetate/methanol (95:5) to give thetitle compound (39 mg, 20% yield). NMR: 2.85-2.98 (m, 4H), 3.15 (s, 3H),3.24-3.30 (m, 2H), 3.51 (q, 2H), 4.82 (t, 1H), 7.10 (dd, 1H), 7.45-7.54(in, 2H), 7.70 (d, 2H), 7.78 (d, 1H), 7.90 (d, 2H), 8.70 (s, 1H), 8.85(s, 1H), 9.72 (d, 1H), 10.18 (s, 1H); m/z: 501 [MH]⁺.

Example 92

[0165] 2-(4{N-[3-(tert-Butoxycarbonylamino)propyl]sulphamoyl}anilino)-4-(imidazo[1,2a]pyrid-3-ylpyrimidine

[0166] 2-Anilino-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine (Example 16; 290mg, 1.0 mmol) was dissolved in thionyl chloride (6 ml) and the mixturewas cooled to 0° C. Chlorosulphonic acid (0.266 ml, 4.0 mmol) was addedslowly and the mixture was stirred at 0° C. for 30 minutes, allowed towarm to ambient temperature stirred for two hours and then heated atreflux for one hour. The volatiles were removed by evaporation. Theresidue was dissolved in dry pyridine (5 ml) and the resulting solutionadded slowly to a solution of 3-(tert-butoxycarbonylamino)propylamine(0.209 ml, 1.2 mmol) and diethylmethylamine (1.21 ml, 10 mmol) inpyridine (10 ml) and cooled to 0° C. under nitrogen. The mixture wasstirred at 0° C. for one hour, then at ambient temperature for twohours. The volatiles were removed by evaporation and the residueazeotroped with water. The residue was triturated with water, collectedby filtration, and then purified by chromatography eluting withdichloromethane/methanol (95:5) increasing in polarity to (90:10) togive the title compound (207 mg, 40% yield). NMR: 1.30 (s, 9H), 1.50(quin, 2H), 2.67 (m, 2H), 2.85 (m, 2H), 7.38 (m, 2H), 7.58 (d, 1H), 7.68(d, 1H), 7.70 (d, 2H), 7.89 (d, 1H), 7.95 (d, 2H), 8.58 (d, 1H), 8.80(s, 1H); m/z: 524 [MH]⁺.

Example 93

[0167]2-(4-{N-[3-(Benzyloxycarbonylamino)propyl]sulphamoyl}anilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0168] 2-Anilino-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine (Example 16; 290mg, 1.0 phenol) and 3-(benzyloxycabonylamino)propylamine (0.294 ml, 1.2mmol) were treated as described in Example 92 to give the title compound(212 mg, 38% yield). NMR: 1.50 (quin, 2H), 2.70 (q, 2H), 2.98 (dd, 2H),4.98 (s, 2H), 7.12-7.15 (m, 4H), 7.18 (t, 2H), 7.19 (t, 1H), 7.75 (d,2H), 7.79 (d, 1H), 7.90 (d, 2H), 8.50 (d, 1H), 8.60 (s, 1H); m/z: 558[MH] ⁺.

Example 94

[0169]2-[4-(2-Diethylaminoethoxy)anilino]-4-(6-phenylimidazo[1,2a]pyrid-3-yl)pyrimidine

[0170] 3-(3-Dimethylaminoprop-2-en-1-oyl)-6-phenylimidazo[1,2a]pyridine(Method 38; 50 mg, 0.17 mmol) was added to a solution of4-(2-diethylaminoethoxy)phenylguanidine (Method 42; 60 mg, 0.19 mmol)and sodium methoxide (11 mg, 0.21 mmol) in n-butanol (1.5 ml) and themixture was heated at 115° C. for 15 hours. The volatiles were removedby evaporation and the residue purified by chromatography eluting withhexanelethyl acetate (50:50) increasing in polarity to ethylacetate/methanol (80:20) to give the title compound (5 mg, 6% yield).NMR: 1.07 (t, 6H), 2.64 (q, 4H), 2,92 (t, 2H), 4.10 (t, 2H), 6.98 (d, 2H), 7.08 (m, 2H), 7.15 (d, 1H), 7.37-7.60 (m, 4H), 7.70 (d, 2H), 7.92(s, 1H), 8.30 (s, 1H), 8.35 (d, 1H), 9.80 (d, 1H); m/z: 479 [MH]⁺.

Example 95

[0171]4-(6-Methoxy-2-methylimidazo[1,2a]pyrid-3-yl)-2-(4-sulphamoylanilino)pyrimidine

[0172]3-(3-Dimethylaminoprop-2-en-1-oyl)-2-methyl-6-methoxyimidazo[1,2a]pyridine(Method 39; 862 mg, 3.51 mmol) was added to a solution of4-sulphamoylphenylguanidine (Method 41; 1.5 g, 7.0 mmol) and sodiummethoxide (758 mg, 14 mmol) in N-butanol (4 ml) and the mixture washeated at reflux for 24 hours. The mixture was allowed to cool and theresulting precipitate collected by filtration and purified bychromatography eluting with hexane/ethyl acetate (50:50) increasing inpolarity to ethyl acetate/methanol (90:10) to give the title compound.NMR: 2.60 (s, 3H), 3.88 (s, 3H), 6.70 (dd, 1H), 7.03 (d, 1H), 7.12 (d,1H), 7.18 (s, 2H), 7.75 (d, 2H), 7.90 (d, 2H), 8.52 (d, 1H), 9.68 (d,1H), 9.97 (s, 1H); m/z: 411 [MH]⁺.

Example 96

[0173] 2-(3-Chloroanilino)-4-(pyrazolo[2,3a]pyrid-3-yl)pyrimidine

[0174] Dry n-butanol (6.0 ml) was added to a mixture of3-(3-dimethylaminoprop-2-en-1-oyl)-2-methylpyrazolo[2,3a]pyridine(Method 18; 180 mg, 0.84 mmol), 3-chlorophenylguanidine (142 mg, 0.84mmol) and sodium hydride (67 mg of a 60% dispersion in mineral oil, 1.67mmol) and the mixture was heated under nitrogen at 125° C. for 7 hours.The volatiles were removed by evaporation and the residue was trituratedwith a mixture of diethylene ether and distilled water. The precipitatedsolid was collected by filtration, washed with diethylene ether anddistilled water and dried to give the title compound (78 mg, 29% yield).NMR: 7.00 (d, 1H), 7.10 (t, 1H), 7.35 (m, 2H), 7.50 (t, 1H), 7.60 (d,2H), 8.08 (s, 1H), 8.43 (d, 1H), 8.70 (d, 1H), 8.82 (d, 2H), 9.68 (s,1H); m/z: 322 [MH]⁺.

Example 97

[0175] 2-Anilino-5-bromo-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0176] 2-Amino-5-bromo-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine (Method 31;200 mg, 0.67 mmol) and bromobenzene (0.08 ml, 0.76 mmol) were treated asdescribed in Example 71 and the product was purified by chromatographyeluting with hexane/ethyl acetate (50.50) increasing in polarity to(0:100) to give the title compound. NMR: 6.98-7.10 (m, 2H), 7.30 (dd,2H), 7.50 (dd, 1H), 7.66 (d, 2H), 7.78 (d, 1H), 8.64 (s, 2H), 8.72 (s,1H), 9.01 (d, 1H), 9.82 (s, 1H).

Example 98

[0177] 2-Anilino-4-(5-bromoimidazo[1,2a]pyrid-3-yl)pyrimidine

[0178] 2-Amino(5-bromoimidazo[1,2a]pyrid-3-yl)pyrimidine (Method 35; 1.0g, 3.4 mmol), and bromobenzene (4.36 ml, 4.1 mmol) were treated asdescribed in Example 71 and the product purified by chromatographyeluting with ethyl acetate/methanol (98:2) increasing in polarity to(90:10) to give the title compound (70 mg; 6% yield) NMR: 7.00 (dd, 1H),7.30-7.40 (m, 4H), 7.59 (d, 1H), 7.65-7.75 (m, 3H), 8.42 (d, 1H), 8.60(s, 1H), 9.70 (s, 1H); m/z: 364 [M−H]⁻.

Example 99

[0179] 2-(4-Morpholinoanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0180] To a solution of 4-morpholinoaniline (192 mg, 1.08 mmol) inN,N-dimethylformamide (2 ml) was added sodium hydride (54 mg of a 60%suspension in mineral oil, 1.35 mmol), and the resulting brownishsuspension was allowed to stir for ten minutes at room temperature. Tothis mixture was added 4-(imidazo[1,2a]pyrid-3-yl)-2-ethylthiopyrimidine(131 mg, 0.539 mmol), and the reaction mixture was heated at 130° C. for3 h. The solvent was removed in vacuo, and the residue was suspended inwater. The obtained solid was filtered off and washed with water,several portions of diethyl ether, and ethyl acetate to afford 46 mg(22% yield) of the title compound as a brownish solid: mp (decomp)>250°C.; ¹H NMR (400 MHz, DMSO-d₆) δ 10.06 (broad s, 1H), 9.44 (s, 1H), 8.60(s, 1H), 8.38 (d, J=5.3 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.56 (d, J=8.5Hz, 2H), 7.51-7.46 (m, 1H), 7.33 (d, J=5.4 Hz, 1H), 7.11-7.02 (m, 1H),6.97 (d, J=8.9 Hz, 2H), 3.78-3.74 (m, 4H), 3.10-3.06 (m, 4H); ¹³C NMR(400 MHz, DMSO-d₆)) δ 160.9, 158.1, 157.8, 148.9, 148.5, 138.3, 132.2,129.7, 126.9, 123.8, 122.2, 118.2, 116.8, 113.7, 107.4, 67.4, 50.4; MS(EI) m/z (relative intensity) 372 (100, M⁺), 313 (30).

Example 100

[0181] 2-(4-Ethoxyanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0182] The title compound was prepared from4-(imidazo[1,2a]pyrid-3-yl)-2-methylthiopyrimidine and 4-ethoxyanilinefollowing the general method of Example 1 affording 20 mg (15% yield) ofthe title compound as a solid: ¹H NMR (400 MHz, DMSO-d₆)) δ 10.07 (broads, 1H), 9.48 (s, 1H), 8.60 (s, 1H), 8.39 (d, J=5.3 Hz, 1H), 7.77 (d,J=8.9 Hz, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.52-7.46 (m, 1H), 7.34 (d, J=5.3Hz, 11H), 7.12-7.08 (m, 1H), 6.93 (d, J=9.0 Hz, 2H), 4.02 (q,J=7.0 Hz,2H), 1.34 (t, J=6.9 Hz, 3H); MS (ESP) m/z 332 (M+1).

Example 101.

[0183] 2-(3,5-Dimethoxyanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0184] The title compound was prepared from4-(imidazo[1,2a]pyrid-3-yl)-2-methylthiopyrimidine and3,5-dimethoxyaniline following the general method of Example 1. Anadditional purification of the product was performed by columnchromatography on silica gel using chloroform/ethanol, 98:2, as theeluent affording 9 mg(6% yield) of the title compound as a greyishsolid: ¹H NMR (400 MHz, CDCl₃) δ 9.93 (d, J=7.0 Hz, 1H), 8.39 (d, J=5.3Hz, 1H), 8.30 (s, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.39-7.34 (m, 1H), 7.18(s, 1H), 7.12 (d, J=5.4 Hz, 1H), 6.97-6.92 (m, 1H), 6.84 (app d, J=2.1Hz, 2H), 6.27 (app t, J=2.2 Hz, 1H), 3.81 (s, 6H); MS (TSP) m/z 348(M+1).

Example 102

[0185]2-(4-Fluoro-3-methylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0186] The title compound was prepared from4-(imidazo[1,2a]pyrid-3-yl)-2-methylthiopyrimidine and4-fluoro-3-methylaniline following the general method of Example 1. Anadditional purification of the product was performed by columnchromatography on silica gel using chloroform/ethanol, 98:2, as theeluent affording 21 mg (12% yield) of the title compound as a paleyellow, solid: ¹H NMR (400 MHz, CDCl₃) δ 9.79 (d, J=7.0 Hz, 1H), 8.36(d, J=5.4 Hz, 1H), 8.30 (s, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.44 (dd,J=6.7, J=2.6 Hz, 1H), 7.38-7.26 (m, 3H), 7.10 (d, J=5.4 Hz, 1H), 7.03(app t, J=8.9 Hz, 1H), 6.89-6.85 (m, 1H), 2.32 (s, 3H); ¹³C NMR (CDCl₃)δ 160.2, 157.8 (d, J_(F)=242 Hz), 157.6, 157.4, 148.6, 138.0, 134.8 (d,J_(F)=2.8 Hz), 129.1, 126.6, 125.3 (d, J_(F)=18 Hz), 124.7 (d, J_(F)=4.7Hz), 121.7, 120.6 (d, J_(F)=7.8 Hz), 117.8, 115.1 (d, J_(F)=23 Hz),113.4, 107.3, 14.8 (d, J_(F)=3.3 Hz); MS (TSP) m/z 320 (M+1).

Example 103

[0187] 2-(4-Cyanoanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0188] The title compound was prepared from4-(imidazo[1,2a]pyrid-3-yl)-2-methylthiopyrimidine and4-aminobenzonitrile following the general method of Example 1 affording120 mg (85% yield) of the title compound as an off-white solid: mp>300°C.; ¹H NMR (400 MHz, DMSO-d₆)) δ 10.24 (s, 1H), 10.12 (d, J=7.0 Hz, 1H),8.68 (s, 1H), 8.54 (d, J=5.5 Hz, 1H, 8.01 (d, J=8.7 Hz, 2H), 7.82-7.77(m, 3H), 7.57-7.52 (m, 2H), 7.257.20 (m, 1H); MS (TSP) m/z 313 (M+1).

Example 104

[0189] 2-(4-Carbamoylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0190] A solution of2-(4-cyanoanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine (34 mg, 0.109mmol) in conc. sulfuric acid (0.5 ml) was stirred at room temperaturefor 2.5 days. The mixture was cooled on ice, and water was addedfollowed by dropwise addition of 45% NaOH solution. The resulting solidwas filtered off and washed with water and diethyl ether. The collectedsolid was air-dried affording 30 mg (83% yield) of the title compound asa brown-white solid: mp>300° C.; ¹H NMR (400 MHz, DMSO-d₆)) δ 10.15 (d,J=6.9 Hz, 1H), 9.97 (s, 1H), 8.66 (s, 1H), 8.51 (d, J=5.4 Hz, 1H),7.90-7.78 (m, 6H), 7.55-7.50 (m, 1H), 7.49 (d, J=5.4 Hz, 1H), 7.21-7.17(m, 2H); ¹³C NMR (400 MHz, DMSO-d₆)) δ 169.2, 160.8, 159.0, 158.6,149.6, 144.8, 140.5, 131.0, 129.9, 128.7, 128.6, 122.6, 119.6, 119.0,115.5, 109.4; MS (TSP) m/z 331 (M+1).

Example 105

[0191] 2-(3-Cyanoanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0192] The title compound was prepared from4-(imidazo[1,2a]pyrid-3-yl)-2-methylthiopyrimidine and3-aminobenzonitrile following the general method of Example 1 affording102 mg (61% yield) of the title compound as a brown-red solid: ¹H NMR(400 MHz, DMSO-d₆)) δ 10.12-10.08 (m, 2H), 8.66 (s, 1H), 8.52 (d, J=5.4Hz, 1H), 8.38 (s, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.80 (d, J=9.0 Hz, 1H),7.58-7.43 (m, 4H), 7.19 (app t, J=6.8 Hz, 1H); ¹³C NMR (400 MHz,DMSO-d₆)) δ 160.9, 159.2, 158.9, 149.9, 143.2, 140.9, 131.9, 131.1,129.0, 126.7, 125.5, 123.3, 122.8, 121.0, 119.3, 115.8, 113.3, 110.0; MS(TSP) m/z 313 (M+1).

Example 106

[0193] 2-(3,5-Difluoroanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0194] The title compound was prepared from4-(imidazo[1,2a]pyrid-3-yl)-2-methylthiopyrimidine and3,5-difluoroaniline following the general method of Example 1. Anadditional purification of the product was performed by columnchromatography on silica gel using chloroform/ethanol, 98:2, as theeluent affording 35 mg (20% yield) of the title compound as a paleyellow solid: ¹H NMR (400 MHz, DMSO-d₆)) δ 10.11-10.09 (m, 2H), 8.66 (s,1H), 8.52 (d, J=5.5 Hz, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.59-7.51 (m, 4H),7.18 (app t, J=6.7 Hz, 1H), 6.82-6.76 (m, 1H); ¹³C N (400 MHz, DMSO-d₆))δ 161.9 (dd, J_(F)=242, J_(F)=16 Hz), 158.2, 156.5, 156.3, 147.3, 142.4(t, J_(F)=14 Hz), 138.3, 128.5, 126.4, 120.2, 116.7, 113.1, 107.6, 100.7(dd, J_(F)=21, J_(F)=8.5 Hz), 95.5 (t, J_(F)=26 Hz); MS (TSP) m/z 324(M+1).

[0195] Preparation of Starting Materials

[0196] The starting materials for the Examples above are eithercommercially available or are readily prepared by standard methods fromknown materials. For example the following reactions are illustrationsbut not limitations of the preparation of some of the starting materialsused in the above reactions.

[0197] Method 1

[0198] 4-(2-Methylimidazo[1,2a]pyrid-3-yl)-2-methylthiopyrimidine

[0199] A mixture of3-(3-dimethylaminoprop-2-en-1-oyl)-2-methylmidazo-[1,2a]pyridine (Method2) (20 g, 87 mmol), thiourea (6.52 g, 86 mmol) and sodium methoxide(1.19 g, 22 mmol) in butanol (220 ml) was heated at 85° C. for two hoursunder nitrogen. Methyl iodide (2 ml, 32 mmol) was added and the mixtureheated at 85° C. for a further 1 hour. Methanol was added and thevolatiles were removed by evaporation. The residue was purified bychromatography eluting with ethyl acetate/methanol (100:0 increasing inpolarity to 97:3) to give the tide compound (16 g, 71% yield). NMR: 2.59(s, 1H), 2.62 (s, 3H), 7.10 (dd, 1H), 7.40 (dd, 1H), 7.42 (d, 1H), 7.63(d, 1H), 8.62 (s, 1H), 9.54 (d, 1H), m/z: 257 [MH]⁺.

[0200] Method 2

[0201] 3-(3-Dimethylaminoprop-2-en-1-oyl)-2-methylimidazo[1,2a]pyridine

[0202] A mixture of 3-acetyl-2-methylimidazo[1,2a]pyridine (Method 3)(40 g, 0.23 mol) and DMFDMA (200 ml) was heated at reflux under nitrogenfor 4 days. The volatiles were removed by evaporation, the residue wastriturated with hot diethylene ether and the solid product collected byfiltration to give the title compound (21 g, 40% yield). NMR: 2.64 (s,3H), 3.29 (s, 6H), 5.50 (d, 1H), 7.00 (dd, 1H), 7.38 (dd, 1H), 7.54 (d,1H), 7.70 (d, 1H), 9.55 (d, 1H), m/z: 230 [MH]⁺.

[0203] Method 3

[0204] 3-Acetyl-2-methylimidazo[1,2a]pyridine

[0205] A mixture of 2-aminopyridine (60 g, 0.64 mol) and3-chloro-2,4-pentanedione (101.4 g, 0.75 mol) in diethylene ether (450ml) and TBF (750 ml) was heated at reflux for 12 hours, then left tostand at ambient temperature for 18 hours. The solvent was removed byevaporation and the residue was purified by chromatography eluting withdichloromethane/hexane (1:1) increasing in polarity todichloromethane/methanol (98:2). The purified product was trituratedwith hexane to give the title compound (46.2 g, 40% yield). NMR: 2.55(s, 3H), 2.68 (s, 3H), 7.15 (dd, 1H), 7.56 (dd, 1H), 7.64 (d, 1H), 9.58(d, 1H, m/z: 175 [MH]⁺.

[0206] Method 4

[0207] 4-(Imidazo[1,2a]pyrid-3-yl)-2-methylthiopyrimidine

[0208] A mixture of3-(3-dimethylaminoprop-2-en-1-oyl)imidazo[1,2a]pyridine (Method 5) (0.90g, 4.2 mmol), thiourea (0.32 g, 4.2 mmol) and sodium methoxide (0.34 g,6.3 mmol) was heated at 85° C. in N-butanol (10 ml) for 2 hours. Themixture was allowed to cool to 30° C., methyl iodide (0.6 ml, 9.6 mmol)was added dropwise and stirring continued for a further 3 hours. Thevolatiles were removed by evaporation and the residue purified bychromatography, eluting with ethyl acetate/methanol (100:0 increasing inpolarity to 97:3) to give the title compound (0.94 g, 93% yield). NMR:2.61 (s, 3H), 7.22 (dd, 1H), 7.54 (dd, 1H), 7.72 (d, 1H), 7.77 (d, 10H.8.56 (d, 1H), 8.66 (s, 1H), 9.83 (d, 1H); m/z: 243 [MH]⁺.

[0209] Method 5

[0210] 3-(3-Dimethylaminoprop-2-en-1-oyl)imidazo[1,2a]pyridine

[0211] A mixture of crude 3-acetylimidazo[1,2a]pyridine (Method 6) (3.3g, 19.1 mmol) and DMFDMA (40 ml) was heated at reflux for 60 hours. Themixture was allowed to cool, the volatiles were removed by evaporationand the residue triturated with hot diethylene ether. The solid productwas collected by filtration to give the title compound (2.29 g, 52%yield). NMR: 2.90 (br s, 3H), 3.10 (br s, 3H), 5.81 (d, 1H), 7.09 (dd,1H), 7.42 (dd, 1H), 7.65 (d, 1H), 7.70 (d, 1H), 8.43 (s, 1H), 9.72 (d,1H); m/z: 216 [MH]⁺.

[0212] Method 6

[0213] 3-Acetylimidazo[1,2a]pyridine

[0214] Aluminium chloride (20.4 g, 153.2 mmol) was added in smallportions to a solution of imidazo[1,2a]pyridine (8.9 g, 75.7 mmol) indichloromethane (150 ml) cooled at 5° C. The mixture was then allowed towarm to ambient temperature and stirred for 1 hour and then heated toreflux. Acetic anhydride (5.1 ml, 53.9 mmol) was then added slowly over30 minutes and the mixture heated at reflux for further 90 minutes. Themixture was allowed to cool, the solvent was removed by evaporation andice/water added to the residue. The aqueous mixture was made alkalinewith 2 M aqueous sodium hydroxide solution and extracted with ethylacetate. The combined extracts were dried and the volatiles removed byevaporation to give a brown oil. This oil was shown to consist of ˜35%of the title compound, the remainder being imidazo[1,2a]pyridine. Thismixture was used without further purification. NMR: 2.57 (s, 3H), 7.22(dd, 1H), 7.61 (dd, 1H), 7.79 (d, 1H), 8.60 (s, 1H), 9.52 (d, 1H).

[0215] Method 7

[0216] 4-(3,5-Dioxapineridin-1-yl)sulphonylaniline

[0217] A mixture of 1-(3,5-dioxapiperidin-1-yl)sulphonyl-4-nitrobenzene(Method 8) (500 mg, 1.82 mmol) and 10% palladium on charcoal catalyst(150 mg) in ethanol (25 ml) and ethyl acetate (25 ml) was stirred underan atmosphere of hydrogen for 3 hours. The catalyst was removed byfiltration through diatomaceous earth and the filter pad was washed withethanol and ethyl acetate. The volatiles were removed from the filtrateby evaporation and the residue triturated with diethylene ether andhexane to give the title compound (395 mg, 88% yield). NMR: 4.90 (s,2H), 5.10 (s, 4H), 6.02 (s, 2H), 6.58 (d, 2H), 7.50 (d, 2H).

[0218] Method 8

[0219] 1-(3,5-Dioxaiperidin-1-yl)sulphonyl-4-nitrobenzene

[0220] 4-Nitrobenzenesulphonamide (2.02 g, 10 mmol) was added to asolution of 1,3,5-trioxane (1.96 g, 20 mmol) in acetic acid (5 ml). Themixture was stirred for 5 minutes and methanesulphonic acid (10 ml) wasadded slowly. The mixture was then stirred at 35° C. for 20 minutes,cooled to 0° C., diluted with water and extracted with ethyl acetate.The combined extracts were washed twice with water and twice with 5%aqueous sodium hydrogen carbonate solution, and then dried and thevolatiles removed by evaporation. The residue was recrystallized fromethanol to give the title compound (955 mg, 35% yield). NMR: 4.87 (s,2H), 5.30 (s, 4H), 8.20 (d, 2H), 8.42 (d, 2H).

[0221] Method 9

[0222] 4-(2-Diethylaminoethoxy)aniline

[0223] A mixture of 4-(2-diethylaminoethoxy)-1-nitrobenzene (Method 10)(1.0 g, 4.2 mmol) and 10% palladium on charcoal catalyst (200 mg) inethanol (30 ml) was stirred under an atmosphere of hydrogen for 3 hours.The catalyst was removed by filtration through diatomaceous earth andthe filter pad was washed with methanol. The volatiles were removed fromthe filtrate by evaporation to give the title compound (400 mg, 46%yield) as an oil. M/z: 209 [MH]⁺.

[0224] Method 10

[0225] 4-(2-Diethylaminoethoxy)-1-nitrobenzene

[0226] Water (8 ml) and xylene (35 ml) were added to a mixture of sodium4-nitrophenoxide (10.5 g, 65 mmol), 2-(diethylamino)ethylchloridehydrochloride (8.6 g, 50 mmol) and potassium carbonate (10.4 g, 75 mmol)and the resulting mixture was heated at reflux for 2 hours. A Dean-Starkapparatus was then fitted and the water was removed. The organicsolution was allowed to cool to ambient temperature and left to standfor 18 hours. The solution was decanted from the precipitated solid andthe volatiles were removed from the decanted solution by evaporation togive the title compound (8.0 g, 52% yield) as an oil. NMR: 0.90 (t, 6H),2.50 (q, 2H), 2.89 (t, 2H), 4.15 (t, 2H), 7.15 (d, 2H), 8.18 (d, 2H);m/z: 239 [MH]⁺.

[0227] Method 11

[0228] 4-[3-(N,N-Dimethyl)amino-2-hydroxypropoxy]aniline

[0229] 3-N,N-Dimethylamino-2-hydroxy-3-(4-nitrophenoxy)propane (Method12) (3.75 g) was dissolved in ethanol (40 ml). Under an atmosphere ofnitrogen, 10% palladium-on-carbon (0.4 g) was added. The nitrogenatmosphere was replaced by one of hydrogen and the reaction mixture wasstirred overnight. The catalyst was removed by filtration throughdiatomaceous earth and the filtrate was evaporated to dryness. Theresidue was dissolved in diethyl diethylene ether containing a smallamount of isopropanol and hydrogen chloride solution (1M in diethyleneether, 16 ml) was added. The diethylene ether was evaporated and thesolid residue was suspended in isopropanol. This mixture was heated on asteam bath for several minutes then allowed to cool to ambienttemperature. The resulting powder was collected by filtration, washedwith isopropanol, diethylene ether and dried (3.04 g, 72.4% yield). NMR:2.80 (s, 6H), 3.15 (m, 2H), 3.88 (m, 2H), 4.25 (m, 1H), 5.93 (br S, 1H),6.88 (m, 4H); m/z 211 [MH]⁺; EA C₁₁Hg₁₈N₂O₂. 1.6 HCl requires C; 49.2,H; 7.4, N; 10.4, Cl; 21.7%: found: C; 49.2, H; 7.2, N; 10.1; Cl; 19.1%.

[0230] Method 12

[0231] 3-N,N-Dimethylamino-2-hydroxy-1-(4-nitrophenoxy)propane

[0232] 1-(4-Nitrophenoxy)-2,3-epoxypropane (Method 13) (4.3 g) wasdissolved in methanol (30 ml) and N,N-dimethylformamide (10 ml).Dimethylamine (2 M solution in methanol, 17 ml) was added and themixture was stirred at ambient temperature overnight. The reactionmixture was evaporated to dryness and the residue was dissolved insaturated sodium bicarbonate solution and ethyl acetate. The ethylacetate layer was separated and washed twice with saturated brine, driedover anhydrous sodium sulphate, filtered and evaporated to yield an oilthat slowly crystallised under high vacuum (4.79 g, 89.9% yield). NMR(CDCl₃):2.33 (s, 6H), 2.98 (m, 1H), 2.54 (m, 1H), 4.00 (m, 3H), 7.00 (d,2H), 8.20 (d, 2H); m/z 241 [MH]⁺.

[0233] Method 13

[0234] 1-(4-Nitrophenoxy)-2,3-epoxypropane

[0235] 1-(4-Nitrophenoxy)-2,3-epoxypropane was prepared by an analogousmethod to that described by Zhen-Zhong Lui et. al. in SyntheticCommunications (1994), 24, 833-838. 4-Nitrophenol (4.0 g), anhydrouspotassium carbonate (8.0 g) and tetrabutylammonium bromide (0.4 g) weremixed with epibromohydrin (10 ml). The reaction mixture was heated at100° C. for 1 hour. After cooling to ambient temperature, the reactionmixture was diluted with ethyl acetate and filtered. The filtrate wasevaporated to dryness and the residue was codistilled twice withtoluene. The resulting oil was purified by column chromatography andeluted with ethanol (1.0%):dichloromethane to yield on evaporation anoil that crystallised (4.36 g, 77.7% yield). NMR (CDCl₃): 2.78 (m, 1H),2.95 (m, 1H), 3.38 (m, 1H), 4.02 (dd, 1H), 4.38 (dd, 1H), 7.00 (d, 2H),8.20 (d, 2H); m/z 196 [MH]⁺.

[0236] Method 14

[0237] 2-Methylthio-4-(2,5-dimethylimidazo[1,2a]pyrid-3-yl)pyrimidine

[0238] A mixture of3-(3-dimethylaminoprop-2-en-1-oyl)-2,5-dimethylimidazo[1,2a]pyridine(Method 15) (3.50 g, 14.4 mmol), thiourea (1.09 g, 14.4 mmol) and sodiummethoxide (1.01 g, 18.7 mmol) was heated at 85° C. in 1-butanol (50 ml)for 2 hours. The mixture was allowed to cool to 30° C. and methyl iodide(1.8 ml, 28.8 mmol) was added dropwise and the mixture stirred for afurther 3 hours. The volatiles were removed by evaporation and theresidue purified by chromatography eluting with ethyl acetate/methanol(100:0 increasing in polarity to 97:3) to give the title compound (2.37g, 61% yield). NMR: 2.41 (s, 3H), 2.60 (s, 3H), 2.70 (s, 3H), 7.56 (d,1H), 7.88 (d, 1H), 7.92 (d, 1H), 8.81 (d, 1H), 9.39 (s, 1H); m/z: 271[MH]⁺.

[0239] Method 15

[0240]3-(3-Dimethylaminoprop-2-en-1-oyl)-2,5-dimethylimidazo[1,2a]pyridine

[0241] A solution of 3-acetyl-2,5-dimethylimidazo[1,2,a]pyridine (Method16) (3.60 g, 19.1 mmol) in DMFDMA (20 ml) was heated at reflux for 60hours. The mixture was allowed to cool and the solvent was removed byevaporation. The residue was triturated with hot diethylene ether, thesolid collected by filtration and dried to give the title compound (3.61g, 84% yield). NMR: 2.30 (s, 3H), 2.62 (s, 3H), 2.90 (br s, 3H), 3.10(br s, 3H), 5.48 (d, 1H), 7.22 (dd, 1H), 7.44 (d, 1H), 7.68 (d, 1H),9.39 (dd, 1H).

[0242] Method 16

[0243] 3-Acetyl-2,5-dimethylimidazo[1,2a]pyridine

[0244] 3-Chloro-2,4-pentanedione (6.5 ml, 54.4 mmol) was added to asuspension of 2-amino-4-methylpyridine (5.00 g, 46.3 mmol) and sodiumiodide (10 mg) in THF (60 ml) and the mixture was heated at reflux for16 hours. The reaction mixture was allowed to cool and the solvent wasremoved by evaporation. The resulting solid residue was triturated withhot hexane, collected by filtration and dried to give the title compound(3.69 g, 43% yield). NMR: 2.35 (s, 3H), 2.75 (s, 3H), 7.41 (dd, 1H),7.57 (d, 1H), 9.40 (d, 1H); m/z. 189 [MH]⁺.

[0245] Method 17

[0246] 4-(2-Methylpyrazolo[2,3a]pyrid-3-yl)-2-methylthiopyrimidine

[0247] A mixture of3-(3-dimethylaminoprop-2-en-1-oyl)-2-methyl-pyrazolo[2,3a]pyridine(Method 18) (3.89 g, 17 mmol), thiourea (1.27 g, 17 mmol) and sodiummethoxide (0.929 g, 17 mmol) in butanol (45 ml) was heated at 85° C. fortwo hours under nitrogen. Methyl iodide (1.05 ml, 17 mmol) was added andthe mixture heated at 85° C. for a further 2 hours. The volatiles wereremoved by evaporation and the residue was purified by chromatographyeluting with ethyl acetate/methanol (100:0 increasing in polarity to97:3) to give the title compound (3.1 g, 68% yield). NMR: 2.58 (s, 1H),2.68 (s, 3H), 7.04 (dd, 1H), 7.39 (dd, 1H), 7.48 (d, 1H), 8.35 (d, 1H),8.50 (d, 1H), 8.72 (d, 1H); m/z: 257 [MH]⁺.

[0248] Method 18

[0249] 3-(3-Dimethylaminonrop-2-en-1-oyl)-2-methylpyrazolo[2,3a]pyridine

[0250] A mixture of 3-acetyl-2-methylpyrazolo[2,3a]pyridine (Method 19)(2 g, 11.5 mmol) and DMFDMA (10 ml) was heated 110° C. under nitrogenfor 48 hours. The volatiles were removed by evaporation, the residue wastriturated with hot diethylene ether and the solid product collected byfiltration to give the title compound (1.98 g, 75% yield). NMR: 2.60 (s,3H), 3.30 (s, 6H), 5.49 (d, 1H), 6.95 (dd, 1H), 7.38 (dd, 1H), 7.62 (d,1H), 8.10 (d, 1H), 8.62 (d, 1H); m/z: 230 [MH]⁺.

[0251] Method 19

[0252] 3-Acetyl-2-methylpyrazolo[2,3a]pyridine

[0253] Potassium carbonate (53.8 g, 0.39 mol) and then 2,4-pentanedione(24.8 g, 0.25 mol) were added to a solution of 1-aminopyridinium iodide(26.9 g, 0.12 mol) in water (336 ml) and the mixture was heated at 80°C. for 2 hours, allowed to cool to ambient temperature and is left tostand for 18 hours. Water was added and the mixture was extracted towith ethyl acetate. The combined extracts were dried and the volatileswere removed by evaporation. The residue was recrystallized from hothexane and the product collected by filtration. Solvent was removed fromthe filtrate by evaporation and was added to the insoluble residue fromthe recrystallization. This crude mixture was purified by chromatographyeluting with dichloromethane/hexane (1:1) increasing in polarity todichloromethane/methanol (97:3). This product was triturated with hexaneand added to the product obtained from the initial recrystallization togive the title compound (9.6 g, 0.33% yield). NMR: 2.50 (s, 3H), 2.62(s, 3H), 7.09 (dd, 1H), 7.55 (dd, 1H), 8.12 (d, 1H), 8.72 (d, 1H); m/z:175 [MH]⁺.

[0254] Method 20

[0255] 2-Chloro-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0256] A suspension of 2-hydroxy-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine(Method 21; 9.92 g, 46%) in phosphoryl chloride (200 ml) and phosphoruspentachloride (11 g, 53%) was heated at reflux under nitrogen for 24hours. Excess phosphoryl chloride was removed by evaporation, ice waterwas added and the mixture neutralised with 2 M aqueous sodium hydroxidesolution. The aqueous mixture was extracted with ethyl acetate, driedand evaporated to give the title compound (7.42 g, 69% yield). NMR: 7.15(dd, 1H), 7.59 (dd, 1H), 7.80 (d, 1H), 8.05 (d, 1H), 8.64 (d, 1H), 8.79(s, 1H), 9.72 (d, 1H); m/z: 231 [MH]⁺.

[0257] Method 21.

[0258] 2-Hydroxy-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0259] A solution of sodium nitrate (11.04 g, 0.16 mol) in water (100ml) was added to a solution of2-amino-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine (Method 22; 11.27 g, 0.053mol) in 70% acetic acid (330 ml) at 60° C. The mixture was heated at 60°C. for 3 hours, allowed to cool and neutralised with 5M aqueous sodiumhydroxide solution, the resulting precipitate was collected byfiltration, washed quickly with cold water and dried in vacuum oven at50° C. to give the title compound (9.95 g, 89% yield). NMR: 6.98 (d,1H), 7.12 (dd, 1H), 7.55 (dd, 1H), 7.80 (d, 1H), 7.82 (d, 1H), 8.70 (s,1H); m/z: 213 [H]⁺.

[0260] Method 22

[0261] 2-Amino-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0262] A mixture of3-(3-dimethylaminoprop-2-en-1-oyl)imidazo[1,2a]pyridine (Method 5; 20 g,0.093 mol), sodium methoxide (20.1 g, 0.372 mol) and guanidinehydrochloride (22.09 g, 0.233 mol) in n-butanol (1500 ml) and methanol(1000 ml) were heated at reflux for 60 hours. The resulting solution wasdecanted from insoluble material, the volatiles were removed byevaporation and the residue was purified by chromatography eluting withdichloromethane/methanol (97:3) to give the title compound (13 g, 67%yield). NMR: 6.78 (s, 1H), 7.15-7.05 (m, 2H), 7.45 (dd, 2H), 7.70 (d,1H), 8.20 (d, 1H), 8.50 (s, 1H), 10.15 (d, 1H); m/z: 212 [MH]⁺.

[0263] Method 23

[0264] 4-(N-Methylsulphamoyl)aniline

[0265] Methylamine (3 ml of a 33% solution in ethanol) and thentriethylamine (0.159 ml, 1.1 mmol) was added to sulphanilyl fluoride(200 mg, 1.1 mmol), and the mixture heated at 80° C. for 6 hours then atambient temperature for 18 hours. The volatiles were removed byevaporation and the residue azeotroped with toluene to give the titlecompound (160 mg, 76% yield). NMR: 2.30 (s, 3H), 5.85 (s, 2H), 6.60 (d,2H), 7.39 (d, 2H); m/z: 187 [MH]⁺.

[0266] Method 24

[0267] 4-[N-(2-Methoxyethyl)sulphamoyl]aniline

[0268] A mixture of 2-methoxyethylamine (859 mg, 11.4 mmol), sulphanilylfluoride (1.0 g, 5.71 mmol), and triethylamine (1.72 g, 22.9 mmol) inn-butanol (15 ml) was heated at reflux for 18 hours. The mixture wasallowed to cool and the volatiles were removed by evaporation. Theresidue was purified by chromatography eluting with ethyl acetate/hexane(50:50) increasing in polarity to (70:30) to give the title compound(860 mg, 65% yield). NMR: 2.78 (q, 2H), 3.15 (s, 3H), 3.25 (t, 2H), 5.87(s, 2H), 6.58 (d, 2H), 7.10 (t, 1H), 7.40 (d, 2H); m/z: 231[MH]⁺.

[0269] Method 25-26

[0270] The following compounds were prepared using the procedure ofMethod 24, Meth Compound Name NMR m/z 25 4-(N-Propylsulphamoyl) 0.78(t,3H), 1.40-1.25 aniline (m, 2H), 2.60(q, 2H), 5.84(s, 2H), 6.59(d, 2H),7.00(t, 1H), 7.39(d, 2H) 26 4-(N-Cyclopropylsulphamoyl) 0.01-0.15(m,4H), 211 aniline 1.70-1.75(m, 1H), [M-H]- 5.60(s, 2H), 6.30(d, 2H), 7.05(s, 1H), 7.10(d, 2H)

[0271] Method 27

[0272] 1-[3-(4-Bromobenzoylamino)propyl]imidazole

[0273] 1-(3-Aminopropyl)imidazole (2.39 ml, 0.02 mol) was added to asolution of 4-bromobenzoyl chloride (4.0 g, 0.018 mol) in ethanol (250ml). The mixture was stirred at ambient temperature for 18 hours. Thevolatiles were removed by evaporation and the residue was purified bychromatography eluting with hexane/dichloromethane (50:50) increasing inpolarity to dichloromethane/methanol (80:20) to give the title compound.NMR: 1.95 (m, 2H), 3.20 (q, 2H), 4.0 (t, 2H), 6.87 (s, 1H), 7.19 (s,1H), 7.64 (d, 2H), 7.68 (s, 1H), 7.78 (d, 2H), 8.58 (t, 1H); m/z: 308[MH]⁺.

[0274] Method 28

[0275] 1-[3-(4-Bromobenzoylamino)propyl]-2-oxopyrolidine

[0276] 1-(3-Aminopropyl)-2-oxopyrolidine (3.07 ml 14 mmol) was treatedas described in Method 27 to give the title compound. NMR: 1.68 (quin,2H), 1.90 (quin, 2H), 2.0 (t, 2H), 3.15-3.22 (m, 4H), 3.29-3.33 (m, 2H),7.64 (d, 2H), 7.78 (d, 2H), 8.48 (t, 1H).

[0277] Method 29

[0278] 2,4-Dichloro-1-(2-methoxyethylsulphamoyl)benzene

[0279] 2,4-Dichlorobenzenesulphonylchloride (500 mg 2.1 mmol) and2-methoxyethylamine (230 mg, 3.1 mmol) in n-butanol (10 ml) was heatedat reflux for one hour. The volatiles were removed by evaporation andresidue purified by chromatography eluting with hexane/ethyl acetate(50:50) to give the title compound. NMR: 3.04 (t, 2H), 3.08 (s, 3H),3.22 (t, 2H), 7.60 (dd, 1H), 7.82 (d, 1H), 7.92 (d, 1H), 8.0 (s, 1H);m/z: 282 [M−H]⁻.

[0280] Method 30

[0281] 2,4-Dichloro-1-(1-propylsulphamoyl)benzene

[0282] 2,4-Dichlorobenzenesulphonyl chloride (500 mg 2.1 mmol) and1-propylamine (0.2 ml, 2.4 mmol) in n-butanol (10 ml) was heated atreflux for 48 hours. The volatiles were removed by evaporation and theresidue triturated with diethylene ether and the product collected byfiltration to give the title compound. NMR: 0.78 (t, 3H), 1.35 (q, 2H),2.79 (t, 2H), 7.60 (dd, 1H), 7.84 (d, 1H), 7.92 (d, 2H)

[0283] Method 31

[0284] 2-Amino-5-bromo-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine

[0285] Bromine (54 ml, 0.0011 mmol) was added dropwise to a solution of2-amino-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine (Method 22; 200 mg, 0.95mmol) in acetic acid (4 ml) at ambient temperature. The mixture washeated at 65° C. for 90 minutes and allowed to cool. The resultingprecipitate was collected by filtration, washed with hexane and dried togive the title compound. NMR: 7.44 (dd, 1H), 7.90-8.00 (m, 2H), 8.59 (s,1H), 8.99 (s, 1H), 9.78 (d, 1H); m/z: 290 [MH]⁺.

[0286] Method 32

[0287] 5-Bromoimidazo[1,2a]pyridine

[0288] A solution of bromoacetaldehyde diethylapetyl (50 ml, 0.332 mol)in dioxane (143 ml), water (85 ml) and conc. hydrochloric acid (5 ml)was heated at reflux for 30 minutes and the mixture allowed to cool.Sodium hydrogen carbonate (53 g) was added followed by a solution of5-bromo-2-aminopyridine (30 g, 0.174 mol) in dioxane (230 ml) and water(85 ml) and the mixture was heated at reflux for 24 hours. The mixturewas allowed to cool, poured into water and acidified with 2 Mhydrochloric acid. The mixture was washed with ethyl acetate and theaqueous layer was basified with 2 M aqueous sodium hydroxide solution.The aqueous mixture was extracted with ethyl acetate. The extracts werecombined, dried and the volatiles removed by evaporation. The residuewas purified by chromatography eluting with hexane/ethyl acetate (50:50)in creasing in polarity (25:50) to give the title compound (20 g, 59%yield). NMR: 7.30 (dd, 1H), 7.54 (d, 1H), 7.59 (s, 1H), 7.90 (s, 1H),8.89 (s, 1H); m/z: 197 [MH]⁺.

[0289] Method 33

[0290] 3-Acetyl-5-bromoimidazo[1,2a]pyridine

[0291] Aluminium chloride (10.2 g, 77 mmol) was added in portions over10 minutes to a solution of 5-bromoimidazo[1,2a]pyridine (Method 32; 5.0g, 26 mmol) in dichloromethane (100 ml) cooled to 0° C. The mixture washeated to reflux and acetyl chloride (2.54 ml, 36 mmol) was added over15 minutes. The mixture was heated at reflux for 24 hours, cooled to 0°C., and further aluminium chloride (10.2 g, 77 mmol) followed by acetylchloride (3.26 ml) were added. The mixture heated at reflux for 24 hoursand then the volatiles were removed by evaporation. Iced water wasadded, the mixture was basified with 2 M aqueous sodium hydroxidesolution and extracted with ethyl acetate. The extracts were washed withwater, dried and the solvent evaporated to the title compound, which wasused without further purification (4.0 g). NMR: 2.58 (s, 3H), 7.74-7.82(m, 2H), 8.62 (s, 1H), 9.62 (s, 1H); m/z: 241 [MH]⁺

[0292] Method 34

[0293] 5-Bromo-3-(3-dimethylaminoprop-2-en-1-oyl)imidazo[1,2a]pyridine

[0294] 3-Acetyl-5-bromoimidazo[1,2a]pyridine (Method 33; 4.0 g) wasdissolved in DMFDMA (200 ml) and the mixture was heated at reflux undernitrogen for 72 hours. The excess DMFDMA was removed by evaporation andthe residue triturated with hot diethylene ether, collected byfiltration and washed with diethylene ether to give the title compound(2.6 g, 53% yield). NMR: 2.90 (s, 3H), 3.12 (s, 1H), 5.82 (d, 1, H),7.58 (dd, 1H), 7.64 (d, 1H), 7.70 (s, 1H), 8.44 (s, 1H), 9.90 (s, 1H);m/z: 294 [MH]⁺.

[0295] Method 35

[0296] 2-Amino-4-(5-bromoimidazo[1,2a]pyrid-3-yl)pyrimidine

[0297] A mixture of5-bromo-3-(3-dimethylaminoprop-2-en-1-oyl)imidazo[1,2a]pyridine (Method34; 2.5 g, 8.5 mmol) guanidine hydrochloride (2.01 g, 21 mmol) andsodium methoxide (1.83 g, 34 mmol) in n-butanol(140 ml) and methanol (45ml) was heated at reflux for 18 hours. The volatiles were removed byevaporation and the residue purified by chromatography eluting withdichloromethane/methanol (95:5) to give the title compound (1.1 g, 45%yield). NMR: 6.86 (s, 2H), 7.12 (d, 1H), 7.57 (dd, 1H), 7.68 (d, 1H),8.22 (d, 1H), 8.51 (s, 1H); m/z: 290 [MH]⁺.

[0298] Method 36

[0299] 6-Phenylimidazo[1,2a]pyridine

[0300] 2-Amino-4-phenylpyridine (0.90 g, 5.29 mmol) was treated asdescribed in Method 32 to give the title compound. NMR: 7.07 (d, 1H),7.35-7.53 (m, 4H), 7.59 (s, 1H), 7.64 (d, 2H), 7.83 (s, 1H), 8.18 (d,1H); m/z: 195 [MH]⁺.

[0301] Method 37

[0302] 3-Bromo-6-phenylimidazo[1,2a]pyridine

[0303] A solution of bromine (0.24 ml, 4.6 mmol) in water (10 ml) wasadded to a solution of 6-phenylimidazo[1,2a]pyridine (Method 36; 0.85 g,4.88 mmol) in ethanol (15 ml) and the mixture stirred for 14 hours inthe dark. The mixture was basified with aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The extracts weredried, the solvent removed by evaporation and the residue trituratedwith diethylene ether and collected by filtration to give the titlecompound. NMR: 7.38-7.56 (m, 4H), 7.77 (s, 1H), 7.83 (d, 2H), 7.96 (s,1H), 8.39 (d, 1H); m/z: 273 [MH]⁺.

[0304] Method 38

[0305] 3-(3-Dimethylaminoprop-2-en-1-oyl)-6-phenylimidazo[1,2a]pyridine

[0306] Phenylmagnesium bromide (2.7 ml of a 1M solution in THF) wasadded to a solution of 3-bromo-6-phenylimidazo[1,2a]pyridine (Method 37;0.48 g, 1.76 mmol) in THF under nitrogen and the mixture was heated atreflux for 2 hours. The mixture was cooled to 0° C. andN-methoxy-N-methylacetamide (0.3 ml 2.64 mmol) was added dropwise. Themixture was allowed to warm to ambient temperature and stirred for 18hours. The reaction mixture was diluted with diethylene ether, washedwith aqueous sodium hydrogen carbonate solution, then brine dried andthe volatiles removed by evaporation. The residue was dissolved inDMFDMA (10 ml) and the mixture heated at reflux under nitrogen for 60hours. The excess DMFDMA was removed by evaporation and the residuetriturated with hot diethylene ether, collected by filtration and washedwith diethylene ether to give the title compound (170 mg, 33% yield).NMR: 2.8-3.2 (br d, 6H), 5.85 (d, 1H), 7.38-7.58 (m, 4H), 7.67 (d, 1H),7.86 (d, 2H), 8.00 (s, 1H), 8.48 (s, 1H), 9.76 (d, 1H); m/z: 292 [MH]⁺.

[0307] Method 39

[0308]3-(3-Dimethylaminoprop-2-en-1-oyl)-2-methyl-6-methoxyimidazo[1,2a]pyridine

[0309] 3-Acetyl-6-methoxy-2-methylimidazo[1,2a]pyridine (Method 40; 1.49g, 7.3 mmol) and toluenesulphonic acid (5 mg) in DMFDMA (25 ml) washeated at reflux for 20 hours. The excess DMFDMA was removed byevaporation. The residue was triturated with diethylene ether and theproduct collected by filtration to give the title compound. NMR: 2.69(s, 3H), 3.28 (s, 6H), 3.82 (s, 3H), 5.44 (d, 1H), 6.69 (dd, 1H), 6.97(d, 1H), 7.65 (d, 1H), 9.21 (d, 1H); m/z: 260 [MH]⁺.

[0310] Method 40

[0311] 3-Acetyl-6-methoxy-2-methylimidazo[1,2a]pyridine

[0312] A solution of 3-chloroacetoacetone (2.86 ml) in THF (6 ml) wasadded to a solution of 2-amino-4-methoxypyridine (2.71 g, 21.8 mmol) inTHF (14 ml) and the mixture was stirred at ambient temperature for 30minutes and then heated at reflux for 3 hours. The solvent was removedby evaporation and the residue purified by chromatography eluting withdichloromethane/methanol (100:0) increasing in polarity to (97:3). Theproduct was recrystallized from tert-butylmethyl diethylene ether togive the title compound (2.1 g, 47% yield). NMR: 2.05 (s, 3H), 2.63 (s,3H), 3.86 (s, 3H), 6.83 (dd, 1H), 7.07 (d, 1H), 9.20 (d, 1H); m/z: 205[MH]⁺.

[0313] Method 41

[0314] 4-Sulphamoylphenylguanidine.

[0315] A mixture of sulphanilamide (20 g, 0.166 mol), benzoyl cyanamide(34 g, 0.33 mol) in ethanol (60 ml) and concentrated hydrochloric acid(11 ml) was heated on a steam bath until the solvent had evaporated.Water was added and the mixture heated at reflux for 5 minutes. Sodiumhydroxide (14.4 g) was added and the mixture heated at reflux. Themixture was allowed to cool and was adjusted to pH2 with hydrochloricacid and the precipitated solid removed by filtration. The filtrate wasneutralised and the solvent removed by evaporation. The residue wasrecrystallized from water to give the crude title product. m/z: 215[MH]⁺.

[0316] Method 42

[0317] 4-(2-Diethylaminoethoxy)phenylguanidine

[0318] A mixture of 3,5-dimethylpyrazolylformidinium nitrate (0.20 g, 1mmol), 4-(2-diethylaminoethoxy)aniline Method 9; 1.0 g, 4.8 mmol) inwater (1 ml) was heated at reflux for 3 hours. The solvent was removedby evaporation, the residue triturated with hot diethylene ether and theproduct collected by filtration to give crude title compound. NMR: 0.98(t, 6H), 2.57 (q, 4H), 2.79 (t, 2H), 4.00 (t, 2H), 6.99 (d, 2H), 7.15(d, 2H); m/z: 251 [MH]⁺.

[0319] Pharmaceutical Formulations

[0320] According to one aspect of the present invention there isprovided a pharmaceutical formulation comprising a compound of formula(I), as a free base or a pharmaceutically acceptable salt thereof, foruse in the treatment and/or prophylaxis of conditions associated withglycogen synthase kinase-3 inhibition.

[0321] The composition may be in a form suitable for oraladministration, for example as a tablet, pill, syrup, powder, granule orcapsule, for parenteral injection (including intravenous, subcutaneous,intramuscular, intravascular or infusion) as a sterile solution,suspension or emulsion, for topical administration as an ointment, patchor cream or for rectal administration as a suppository.

[0322] In general the above compositions may be prepared in aconventional manner using conventional excipients.

[0323] Suitable daily doses of the compounds of formula (I) in thetreatment of a mammal, including man are approximately 0.01 to about 250mg/kg bodyweight at peroral administration and about 0.001 to 250 mg/kgbodyweight at parenteral administration. The typical daily dose of theactive ingredients varies within a wide range and will depend on variousfactors such as the relevant indication, the route of administration,the age, weight and sex of the patient and may be determined by aphysician.

[0324] The following illustrate representative pharmaceutical dosageforms containing a compound of formula (I), as a free base or apharmaceutically acceptable salt thereof (hereafter compound X), fortherapeutic or prophylactic use in mammals: (a): Tablet I mg/tabletCompound X 100 Lactose Ph.Eur 182.75 Croscarmellose sodium 12.0 Maizestarch paste (5% w/v paste) 2.25 Magnesium stearate 3.0 (b): Tablet IImg/tablet Compound X 50 Lactose Ph.Eur 223.75 Croscarmellose sodium 6.0Maize starch 15.0 Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesiumstearate 3.0 (c): Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur93.25 Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste) 0.75Magnesium stearate 1.0 (d): Capsule mg/capsule Compound X 10 LactosePh.Eur 488.5 Magnesium stearate 1.5 (e): Injection I (50 mg/ml) CompoundX  5.0% w/v 1M Sodium hydroxide solution 15.0% v/v 0.1M Hydrochloricacid (to adjust pH to 7.6) Polyethylene glycol 400  4.5% w/v Water forinjection to 100% (f): Injection II 10 mg/ml Compound X  1.0% w/v Sodiumphosphate BP  3.6% w/v 0.1M Sodium hydroxide solution 15.0% v/v Waterfor injection to 100% (g): Injection III (1 mg/ml,buffered to pH6)Compound X  0.1% w/v Sodium phosphate BP 2.26% w/v Citric acid 0.38% w/vPolyethylene glycol 400  3.5% w/v Water for injection to 100%

[0325] The above formulations may be obtained by conventional procedureswell known in the pharmaceutical art.

[0326] Medical Use

[0327] We have found that the compounds defined in the presentinvention, as a free base or a pharmaceutically acceptable salt thereof,are well suited for inhibiting glycogen synthase kinase-3 (GSK3).Accordingly, the compounds of the present invention are expected to beuseful in the treatment and/or prophylaxis of conditions associated withglycogen synthase kinase-3 activity, i.e. the compounds may be used toproduce an inhibitory effect of GSK3 in mammals, including man in needof such treatment and/or prophylaxis.

[0328] GSK3 is highly expressed in the central and peripheral nervoussystem and in other tissues. Thus, it is expected that a compound of theinvention is well suited for the treatment and/or prophylaxis ofconditions associated with glycogen synthase kinase-3 activity in thecentral and peripheral nervous system. In particular, such compounds ofthe invention are expected to be suitable for treatment and/orprophylaxis of conditions associated with especially, dementia,Alzheimer's Disease, Parkinson's Disease, Frontotemporal dementiaParkinson's Type, Parkinson dementia complex of Guam, HIV dementia,diseases with associated neurofibrillar tangle pathologies, amyotrophiclateral sclerosis, corticobasal degeneration, dementia pugilistica,Down's syndrome, Huntington's Disease, postencephelatic parkinsonism,progressive supranuclear palsy, Pick's Disease, Niemann-Pick's Disease,stroke, head trauma and other chronic neurodegenerative diseases,Bipolar Disease, affective disorders, depression, schizophrenia,cognitive disorders, Type I and Type II Diabetes and Diabeticneuropathy, hair loss and contraceptive medication.

[0329] The dose required for the therapeutic or prophylactic treatmentof a particular disease will necessarily be varied depending on the hosttreated, the route of administration and the severity of the illnessbeing treated.

[0330] Non-Medical Use

[0331] In addition to their use in therapeutic medicine, the compoundsof formula (I), as a free base or pharmaceutically salts are also usefulas pharmacological tools in the development and standardisation of invitro and in vivo test systems for the evaluation of the effects ofinhibitors of GSK3 related activity in laboratory animals such as cats,dogs, rabbits, monkeys, rats and mice, as part of the search for newtherapeutical agents.

[0332] Pharmacology

[0333] Determination of ATP Competition in Scintillation Proximity GSK3βAssay

[0334] GSK3β Scintillation Proximity Assay.

[0335] The competition experiments were carried out in duplicate with 10different concentrations of the inhibitors in clear-bottom microtiterplates (Wallac, Finland). A biotinylated peptide substrate,Biotin-Ala-Ala-Glu-Glu-Leu-Asp-Ser-Arg-Ala-Gly-Ser(PO₃H₂)-Pro-Gln-Leu(AstraZeneca, Lund), was added at a final concentration of 1 μM in anassay buffer containing 1 mU recombinant human GSK3β (Dundee University,UK), 12 nM morpholinepropanesulfonic acid (MOPS), pH 7.0, 0.3 mM EDTA,0.01% β-mercaptorethanol, 0.004% Brij 35 (a natural detergent), 0.5%glycerol and 0.5 ug BSA/25 pi. The reaction was initiated by theaddition of 0.04 pCi [γ-³³P]ATP (Amersham, UK) and unlabelled ATP at afinal concentration of 1 μM and assay volume of 25 μl. After incubationfor 20 minutes at room temperature, each reaction was terminated by theaddition of 25 μl stop solution containing 5 mM EDTA, 50 μM ATP, 0.1%Triton X-100 and 0.25 mg streptavidin coated Scintillation ProximityAssay (SPA) beads (Amersham, UK). After 6 hours the radioactivity wasdetermined in a liquid scintillation counter (1450 MicroBeta Trilux,Wallac). The inhibition curves were analysed by non-linear regressionusing GraphPad Prism, USA. The K_(m) value of ATP for GSK30, used tocalculate the inhibition constants (K_(i)) of the various compounds, was20 μM.

[0336] The following abbreviations have been used: MOPSMorpholinepropanesulfonic acid EDTA Ethylendiaminetetraaceticacid BSABovin Serum Albumin ATP Adenosine Triphophatase SPA ScintillationProximity Assay GSK3 Glycogen synthase kinase 3

[0337] Results

[0338] Typical K_(i) values for the compounds of the present inventionare in the range of about 0.001 to about 10,000 nM. Other values forK_(i) are in the range of about 0.001 to about 1000 nM. Further valuesfor K_(i) are in the range of about 0.001 nM to about 300 nM.

1. Use of a compound of formula (I)

wherein: Ring A is imidazo[1,2a]pyrid-3-yl or pyrazolo[2,3a]pyrid-3-yl;R² is attached to a ring carbon and is selected from halo, nitro, cyano,hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0, 1, or 2, C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl,N,N-(C₁₋₆alkyl)₂sulphamoyl, phenyl, heterocyclic group, phenylthio and,(heterocyclic group)thio; wherein any C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, phenyl or heterocyclic group may be optionally substitutedon carbon by one or more G; and wherein if said heterocyclic groupcontains an —NH— moiety that nitrogen may be optionally substituted by agroup selected from Q; m is 0, 1, 2, 3, 4 or 5; wherein the values of R²may be the same or different; R¹ is halo, nitro, cyano, hydroxy,trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₃alkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, C₁₋₃alkoxy,C₁₋₃alkanoyl, N-(C₁₋₃alkyl)amino, N,N-(C₁₋₂alkyl)₂amino,C₁₋₃alkanoylamino, N-(C₁₋₃alkyl)carbamoyl, N,N-(C₁₋₂alkyl)₂carbamoyl,C₁₋₃alkylS(O)_(a) wherein a is 0, 1 or 2, N-(C₁₋₃alkyl)sulphamoyl orN,N-(C₁₋₃alkyl)₂sulphamoyl; wherein any C₁₋₂alkyl, C₁₋₃alkyl,C₂₋₃alkenyl or C₂₋₃alkynyl may be optionally substituted on carbon byone or more J; n is 0, 1 or 2, wherein the values of R¹ may be the sameor different; Ring B is phenyl or phenyl fused to a C₅₋₇cycloalkyl ring;R³ is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₆alkoxy, p is 0, 12, 3 or 4; wherein the values of R³ may be the same or different; R⁴ isa group A-E-; wherein A is selected from hydrogen, C₁₋₆alkyl, phenyl, aheterocyclic group, C₃₋₈cycloalkyl, phenylC₁₋₆alkyl, (heterocyclicgroup)C₁₋₆alkyl or C₃₋₈cycloalkylC₁₋₆cycloalkyl; which C₁₋₆alkyl,phenyl, a heterocyclic group, C₃₋₈cycloalkyl, phenylC₁₋₆alkyl,(heterocyclic group)C₁₋₆alkyl or C₃₋₈cycloalkylC₁₋₆cycloalkyl may beoptionally substituted on carbon by one or more D; and wherein if saidheterocyclic group contains an —NH— moiety that nitrogen may beoptionally substituted by a group selected from R; E is a direct bond or—O—, —C(O)—, —OC(O)—, —C(O)O—, —N(R^(a))C(O)—, —C(O)N(R^(a))—,—N(R^(a))—, —S(O)_(r)—, —SO₂N(R^(a))— or —N(R^(a))SO₂—; wherein R^(a) ishydrogen or C₁₋₆alkyl optionally substituted by one or more D and r is0, 1 or 2; D is independently selected from oxo, halo, nitro, cyano,hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, C₁ alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylamino, benzyloxycarbonylamino,N-(C₁₋₆alkyl)sulphamoyl and N,N-(C₁₋₆ alkyl)₂sulphamoyl; wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl or phenyl may be optionallysubstituted on carbon by one or more K; q is 0, 1 or 2; wherein thevalues of R⁴ maybe the same or different; and wherein p+q≦5; G, J and Kare independently selected from halo, nitro, cyano, hydroxy,trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto,sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy,methylamino, ethylamino, dimethylamino, diethylamino,N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl,methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl,ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl,N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl andN-methyl-N-ethylsulphamoyl; and Q and R are independently selected fromC₁₋₄alkyl, C₁₋₄alkanoyl, C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonyl,carbamoyl, N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl, or a pharmaceuticallyacceptable salt thereof in the manufacturing of a medicament for thetreatment and/or prophylaxis of conditions associated with glycogensynthase kinase-3 inhibition.
 2. The use according to claim 1, whereinthe condition is selected from the group consisting of dementia,Alzheimer's Disease, Parkinson's Disease, Frontotemporal dementiaParkinson's Type, Parkinson dementia complex of Gaum, HIV dementia,diseases with associated neurofibrillar tangle pathologies, amyotrophiclateral sclerosis, corticobasal degeneration, dementia pugilistica,Down's syndrome, Huntington's Disease, postencephelatic parkinsonism,progressive supranuclear palsy, Pick's Disease, Niemann-Pick's Disease,stroke, head trauma, Bipolar Disease, affective disorders, depression,schizophrenia, cognitive disorders, Type I and Type II Diabetes andDiabetic neuropathy, hair loss and contraceptive medication.
 3. The useaccording to claim 2, wherein the condition is dementia or Alzheimer'sDisease.
 4. Compounds selected from2-(4-Fluoro-3-methylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,2-(4-Cyanoanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidines,2-(4-Chloroanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,2-Anilino-4-(2-methylimidazo[1,2a]pyrid-3-yl)pyrimidine,2-[4-(Pyrimid-2-ylaminosulphonyl)anilino]-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,2-(4-Carbamoylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,2-(3-Cyanoanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,2-(3,5-Difluoroanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,2-(3-Chloroanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine,2-[4-(N,N-Dimethylcarbamoyl)anilino]4-(imidazo[1,2a]pyrid-3-yl)primidine,2-(4-Mesylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine and2-(3-Sulphamoylanilino)-4-(imidazo[1,2a]pyrid-3-yl)pyrimidine, or apharmaceutically acceptable salt thereof.
 5. The use of compoundsaccording to claim 4 in the manufacturing of a medicament for thetreatment and/or prophylaxis of conditions associated with glycogensynthase kinase-3 inhibition.
 6. A pharmaceutical formulation for use inthe treatment and/or prophylaxis of conditions associated with glycogensynthase kinase-3 inhibition, comprising a therapeutically effectiveamount of a compound of formula (I) as defined in claim 1 or apharmaceutically acceptable salt thereof and conventional excipients. 7.The pharmaceutical formulation according to claim 6 for use in thetreatment and/or prophylaxis of dementia, Alzheimer's Disease,Parkinson's Disease, Frontotemporal dementia Parkinson's Type, Parkinsondementia complex of Gaum, HIV dementia, diseases with associatedneurofibrillar tangle pathologies, amyotrophic lateral sclerosis,corticobasal degeneration, dementia pugilistica, Down's syndrome,Huntington's Disease, postencephelatic parkinsonism, progressivesupranuclear palsy, Pick's Disease, Niemann-Pick's Disease, stroke, headtrauma, Bipolar Disease, affective disorders, depression, schizophrenia,cognitive disorders, Type I and Type II Diabetes and Diabeticneuropathy, hair loss or contraceptive medication.
 8. The pharmaceuticalformulation according to claim 6 for use in the treatment and/orprevention of dementia or Alzheimer's Disease.
 9. The pharmaceuticalformulation for use according to any of claims 7 and 8, wherein thecompound is defined as in claim
 4. 10. A method of treatment and/orprophylaxis of conditions associated with glycogen synthase kinase-3inihibition comprising administering to a mammal, including man in needof such treatment and/or prophylaxis a therapeutically effective amountof a compound of formula (I) as defined in claim 1 or a pharmaceuticallyacceptable salt thereof.
 11. The method according to claim 10, whereinthe condition is selected from the group consisting of dementia,Alzheimer's Disease, Parkinson's Disease, Frontotemporal dementiaParkinson's Type, Parkinson dementia complex of Gaum, HIV dementia,diseases with associated neurofibrillar tangle pathologies, amyotrophiclateral sclerosis, corticobasal degeneration, dementia pugilistica,Down's syndrome, Huntington's Disease, postencephelatic parkinsonism,progressive supranuclear palsy, Pick's Disease, Niemann-Pick's Disease,stroke, head trauma, Bipolar Disease, affective disorders, depression,schizophrenia, cognitive disorders, Type I and Type II Diabetes andDiabetic neuropathy, hair loss and contraceptive medication.
 12. Themethod according to claim 10, wherein the condition is dementia orAlzheimer's Disease.
 13. The method according to any one of claims 10 to12, wherein the compound is defined as in claim 4.